2,4-diaryl - substituted [1,8] naphthyridines as kinase inhibitors for use against cancer

ABSTRACT

The present invention relates to novel [1,8]naphthyridine derivatives of formula (I) and to the use of such compounds in which the inhibition, regulation and/or modulation of signal transduction by ATP consuming proteins like kinases plays a role, particularly to inhibitors of TGF-beta receptor kinases, and to the use of such compounds for the treatment of kinase-induced diseases, in particular for the treatment of tumors.

TECHNICAL FIELD

The present invention relates to novel [1,8]naphthyridine derivativesand to the use of such compounds in which the inhibition, regulationand/or modulation of signal transduction by ATP consuming proteins likekinases plays a role, particularly to inhibitors of TGF-beta receptorkinases, and to the use of the compounds for the treatment ofkinase-induced diseases.

PRIOR ART

Proteins which bind ATP and utilize its energy to change conformation,to phosphorylate substrates, and to initiate signaling cascades areknown from many classes, like kinases, phosphatases, chaperones orisomerases. With specific tools and techniques ATP-binding proteins canbe enriched.

From the large family of protein kinases, split into subfamilies oftyrosine kinases and serine threonine kinases, a partial list includescAbl, Akt, ALK, ALK1 and its family members like ALK1 and ALK5, Axl,Aurora A and B, Btk, Dyrk2, EGFR, Erk, Ephrin receptors like EphA2, FAK,FGF receptors like FGFR3, insulin receptor IR and insulin like growthfactor receptor IGF1 R, IKK2, Jak2, JNK3, cKit, LimK, VEGF receptors 1,2, and 3, Mek1, Met, P70s6K, PDGFR, PDK1, PI3K, Plk1, PKD1, bRaf, RSK1,Src and its family members, TAK1, Trk A, B, C, Zap70. The differentkinases can be described under several synonyms, well known to the oneskilled in the art and accessible in data bases like Kinweb to find agene and protein report with alternative names, classification, geneannotation, sequence and gene structure, and links to the pdb 3Dstructure information. Similarly, proteomics server will give access toa lot of information and analysis and prediction tools for genes andproteins, including kinases.

As a mechanistic part of the hallmarks of cancer, Ser/Thr kinases andreceptor tyrosine kinases (RTK) are phosphorylating enzymes essential incellular signaling. Cell cycle, survival, proliferation and cell deathare cellular processes, regulated by cell signaling, to permit tissue togrow, to regenerate and to be in homeostasis, or to regress. Somekinases are therefore exquisite targets for mammalian therapy.

Of the different families of kinases, which are part of the human kinomethe receptor tyrosine kinase KDR, also called VEGF receptor 2, canstimulate endothelial cell survival and proliferation if ligated extracellular by VEGF. Ligand binding can then lead to intracellularphosphorylation events, a signaling cascade and ultimately toproliferation. Inhibition of this KDR signaling is attempted by varioustherapies.

Other kinases and ligands important for function of endothelial cellsare TIE2 kinase and the angiopoietins, PDGF receptor and PDGF as well asPIGF. Ephrin receptor kinase and ephrins, especially EphB4 andephrin-B2. In addition, the ligand TGFβ and its receptors TGFβR, i.e.Alk1/Alk5 play an important role in maintenance of vascular integrity.By binding to the TGFβ type II receptor TGFγ can activate 2 distincttype I receptors in endothelial cells, i.e. the EC-restricted ALK1 andthe broadly expressed ALK5 with opposite effects on EC behavior. ALK1stimulates EC proliferation and migration via Smad1/5 transcriptionfactors, ALK5 inhibits those functions via Smad2/3 transcriptionfactors. One example for an Alk5 kinase inhibitor that facilitates ECproliferation and sheet formation is SB-431542. Ligand bindinginhibition might be an additional approach to modulate TGFβ receptorsignaling also in angiogenesis. This was shown with 2 peptides and alsodiscussed for soluble TGFβ receptors TβR-Fc. Use of anti-TGFβantibodies, even a TGFβ trap, would be another strategy to inhibit TGFβsignaling.

The TGFβ proteins comprise a family of conserved dimeric proteins with amolecular weight of ˜25 kDa, which are ubiquitously expressed andsecreted in an inactive form. Local proteolysis in response toappropriate stimuli leads to active TGFβ ligands. TGFβ signaling isimplicated in numerous conditions and diseases, including cancer,cardiovascular, bone, CNS, PNS, inflammatory and neurodegenerativedisorders.

In epithelial cells, TGFβ inhibits cell proliferation. The transition ofnormal epithelial cell into carcinoma cells is accompanied bydown-regulation of the growth-inhibition response to TGFβ, allowing thecells to escape the autocrine tumor suppressor activities of TGFβsignaling. The increased production of TGFβ by carcinoma cellscontributes to the invasive and metastatic behavior of the cancer cells.TGFβ can induce an epithelial-to-mesenchymal transition (EMT) thatallows the cells to become invasive and migratory. In addition, theincreased TGFβ production exerts effects on stromal and immune cells toprovide a favorable microenvironment for cancer progression. TGFβproteins signal through TβR-I/II receptor kinases and their Smadsubstrates, but can also signal independent of Smads, such as ERK MAPkinases, PI3 kinase, Rho-like GTPases, protein phosphatase 2A, and Par6.Activated type I TβR kinases enhance survival of cells and canaccelerate pathological cell progression.

TGFβ receptor type I and II (TβR I, TβR II) are single-passtransmembrane-spanning intracellular serine/threonine kinases presentingextracellular ligand (TGFβ ) binding receptors. Intra-cellular signalingproceeds via auto-phosphorylation, trans-phosphorylation and substratephosphorylation, leading to modulation of target gene expression.Cloning and genomic organization of TβR proteins is well-known. TβRsequences are deposited in www.uniprot.org as TGFR1_human with accessionnumber P36897, and as TGFβ R2_human with accession number P37173. Onprotein level, type I TβR is described to contain a region rich in Glyand Ser (GS domain) preceeding the receptor kinase domain. TβR II is inits auto/phosphorylated state a constitutively active kinase which bindsto the type I receptor and phosphorylates it in the GS domain.

TβReceptor, a ligand TGFβ -bound (activated) tetrameric complex of 2 TβRI and 2 TβR II units, is able to phosphorylate Smads (Smad 2 and Smad 3)in their C-terminal SSXS motifs as substrates which in turn are boundto/by Smad4 to be translocated to the cell nucleus, where they modulateTGFβ responsive genes. The different domains which regulate homomericand heteromeric complex formation among type I and type II TβRs areknown. Mutations in the GS domain of TβR I can be constitutivelyactivating. Kinase inactivating mutation were found with K232R for typeI and K277R for type II TβR. Inactivating or attenuating mutations inthe genes for Type I and Type II TβR genes are found in a variety ofcancers. In addition, signaling of TβRs is regulated by phosphorylationand dephosphorylation mechanisms, ubiquitinylation and sumoylation, andby endocytosis and by TACE-mediated ectodomain shedding of type I, butnot type II receptors TACE, aka ADAM-17, which mediates shedding ofcytokines, GF receptors, and adhesion proteins and is highly expressedin cancers.

The X-ray co-crystal structure of TβR I and FKBP12 has been described,and the kinase activation process was discussed. Meanwhile, severalcrystal structures can be found in the PDB data base: 1 B6C, 1IAS, 1PY5,1 RW8, 1VJY, 2PJY, and a model 1TBI. For TβR II only X-ray studies forthe extracellular ligand binding domain are known to the public: 1KTZ,1M9Z, and 1PLO (NMR), but none of the kinase domain.

TGFβ signal transduction involves Smads, the only substrates for TβRtype I receptor kinases. The human genome encodes eight Smads from 3subfamilies (R-, Co-, I-Smads), which are ubiquitously expressedthroughout development and in adult tissue. Smads not only arephosphorylated by Type I TGFβ receptor kinases but they are alsoregulated by oligomerisation, ubiquitinylation and degradation, andnucleoplasmatic shuttling.

It was shown that VEGF release is regulated by ALK1 and ALK5, whereasTGFβ enhanced and BMP-9 suppressed expression of VEGF.

Studies with truncated ALK4 isoforms suggest involvement of this type Ikinase in growth and development of pituitary tumors, by a dominantnegative inhibition of activin signaling. Studies of the spatiotemporalwindow of roles of ALK4 in embryonic development, regulation of themesoderm induction, primitive streak formation, gastrulation, primaryaxis formation and left-right axis determination are still notclarifying the role of ALK4 in adult.

In a large scale human candidate screen it was found thatdominant-negative ALK2 alleles are associated with congenital heartdisease, like improper atrioventrikular septum development.

ALK1 binds TβR-II and Endoglin/CD105/TβR-III and phosphorylates SMAD-1and -5. The role of endoglin and especially the differential modulationof TGFβ signaling by two variants, L- and S-endoglin, have been shown.ALK1 functions in vascular remodeling and is found with ALK5 inbalancing the activation state of endothelium in inflamed tissue, woundsand tumor. ALK1 is expressed in lung, placenta, and other highlyvascularized tissue, and is selectively found on ECs. In addition, ALK1was detected on neurons.

Loss of expression of type II TβR correlates with high tumor grade inhuman breast carcinomas, indicating a contribution to beast cancerprogression. Tumor growth can be characterized by deregulated i.e.autonomous cell growth due to perturbation of RTK signaling by mutationsor other genetic alterations. Of the 32000 human coding genes which areinvolved in signal transduction, more than 520 protein kinases and 130protein phosphatases exert tight and reversible control on proteinphosphorylation. Selectivity is found for tyrosine and forserine/threonine phosphorylation. There are more than 90 known PTK genesin the human genome, more than 50 encode transmembrane RPTKs distributedin 20 subfamilies, and 32 encode cytoplasmic, non-receptor PTKs in 10subfamilies. For example Trk A has an important role in thyroidcarcinomas and neuroblastomas, EphB2 and B4 are over-expressed incarcinomas, Axl and Lck are over-expressed in leukemia.

TGFβ inhibitors for the treatment of cancer were reviewed. There arefurther indications and pathologies, indirect targeting cancer, woundhealing and inflammation via anti-angiogenesis, blood vessel formation,stabilization, maintenance and regression.

Angiogenesis, the development of new vessels from pre-existing vessels,is critical in vascular development in embryogenesis, organogenesis, andwound healing. In addition to those physiological processes,angiogenesis is important for tumor growth, metastasis and inflammation,resulting in diseases like tumors of the breast, uterine cervix, uterinecorpus (endometrium), ovary, lung, bronchus, liver, kidney, skin, oralcavity and pharynx, prostate, pancreas, urinary bladder, blood cells,colon, rectum, bone, brain, central and peripheral nervous system,exemplified as breast cancer, colorectal cancer, gliomas, lymphomas, andso on, and of inflammatory diseases like rheumatoid arthritis andpsoriasis, or diseases of the eye, like macula degeneration, anddiabetic retinopathy. Molecular mechanisms of blood vessel formation andthe angiogenic switch in tumorigenesis were recently discussed. Vascularpatterning is regulated by Eph receptor tyrosine kinases and ephrinligands, e.g. ephrin-B2 signaling via Eph B4 and Eph B1. EphB4 controlsvascular morphogenesis during postnatal angiogenesis. The maturation ofnascent vasculature, formed by angiogenesis or vasculogenesis, requiresmural cells (pericytes, smooth muscle cells), generation ofextracellular matrix and specialization of the vessel wall forstructural support and regulation of vessel function. Regulation ofthose processes and interaction between endothelial cells and theirmural cells involves several ligand kinase pairs, like VEGF/VEGFR1,VEGFR2, EphrinB2/EphB4, PDGFR/PDGFRβ, Angiopoietins/TIE2,TGFβ/TGFβR-ALK1/ALK5. Vessel assembly, capillary formation, sprouting,stabilization and destabilization, even regression, is regulated by afunctional balance of those kinases and ligands. Lymphangiogenesis isregulated via VEGF receptor 3 and its ligands VEGF C, and D, as well asTIE2 and its ligands angiopoietins 1, 2. Inhibition of VEGFR3 and/orTIE2 signaling and therefore inhibition of formation of lymphaticvessels can be a mean to stop metastasis of tumor cells. The whole bodyof information about pathological vascularisation leads to theassumption for inhibition of angiogenesis being a promising strategy fortreatment of cancer and other disorders.

The importance of TGFβ receptors for angiogenic processes is shown byAlk1, endoglin, Alk5 and TβRII KO mice all exhibiting an embryoniclethal phenotype due to vascular defects. In addition, in ECs TGFβligands are able to stimulate two pathways, with Smad 1/5/8phosphorylation downstream of Alk1 and Smad2/3 phosphorylationdownstream of Alk5. Both pathways cross-talk with each other. Alk5knock-in mice with L45 loop mutations show defective Smad activation.TGFβ/Alk5 signaling is antagonized by ALK1 in ECs.

TGFβ exists in at least five isoforms (TGFβ1-5), which are not relatedto TGFα, with TGFβ1 as the prevalent form. TGFβ is a ubiquitous andessential regulator of cellular and physiological processes includingproliferation, differentiation, migration, cell survival, angiogenesisand immunosurveillance.

Since cancer cells express tumor-specific antigens they normally wouldbe recognized by the immune system and would be destroyed. Duringtumorigenesis cancer cells acquire the ability to evade thisimmunosurveillance by multiple mechanisms. A major mechanism is cancercell mediated immunosuppression by secretion of TGFβ, a potentimmunosuppressive cytokine. TGFβ has the potential to switch from beinga tumor suppressor to a tumor promoter and prometastatic factor. TGFβfunction is transmitted by a tetrameric receptor complex, consisting oftwo groups of transmembrane serine-threonine kinase receptors, calledtype I and type II receptors, which are activated following engagementof members of the TGFβ superfamily of ligands, which is divided in 2groups, the TGFβ/Activin and BMP/GDF branches. TGFβ1, 2, and 3 belong tothe TGFβ/Activin branch of ligands. These binding events specifydownstream responses that are differentially regulated in different celltypes.

Importance of fibroblasts in mesenchymal-epithelial interaction in skinduring wound repair was described in an inducible postnatal deletion ofTGFβ RII in skin fibroblasts. During wound repair, expression of theligand TGFβ and its receptor types RI and RII are timely and spatiallyregulated. CD109, a GPI linked cell surface antigen, expressed by CD34+acute myeloid leukemia cell lines, ECs, activated platelets and T-cellsare part of the TβR system in human keratinocytes. Follicle Stem Cells(FSCs) in the bulge region of hair follicle can give rise to multiplelineages during hair cycle and wound healing. Smad4, a common mediatorof TGFβ signaling is part of FSCs maintenance. Smad4 KO studies in mouseskin showed hair follicle defects and squamous cell carcinoma formation.The potential suppression of TGFβ delayed catagen progression in hairfollicles. The well described role of TGFβ in keratinocyte apoptosisduring catagen phase is likely to involve anagen-specific hair folliclecomponents also involving co-localized TβRI and TβRII.

Abnormal activity of TGFβ in fibrosis of several organs, such as skin,kidney, heart and liver, is known, being a rational for use of TβRinhibitors in fibrotic diseases. Systemic sclerosis (scleroderma), acomplex disorder of connective tissue leading to fibrosis of the skinand inner organs, was shown to be TGFβ/receptor RI dependent. Pulmonaryarterial hypertension (PAH) is a condition potentially treatable withALK5 inhibitors because abnormal proliferation of peripheral arterialsmooth muscle cells is driven by activated TGFβ receptors. Treatment inrats was successful with SB525334. Benefit in rat was also shown withIN-1233. Renal fibrosis can lead to diabetes.

Beneficial side effects of TβR kinase inhibitor derivatives and aconnection between TGFβ signaling and hepatitis C virus (HCV)replication is known. TGFβ signaling is discussed as an emerging stemcell target in metastatic breast cancer. TGFβ1, 2, 3 and their receptorsare expressed in neurons, astrocytes and microglia. Improvement ofpathological outcome with TGFβ signaling modulators can be expected. TheTGFβ superfamily in cardiovascular disease, like atherosclerosis,myocardial ischemia and cardiac remodeling is focus of an issue ofcardiovascular research.

Further details on the biochemistry of TGFβ are disclosed in WO2009/004753, which is incorporated in its entirety by reference in thedisclosure of the invention hereby.

In addition, RON kinase is a valuable target in tumor biology (Wagh etal. (2008) Adv Cancer Res. 100: 1-33). The Met-related receptor tyrosinekinase RON is involved in tumor growth and metastasis. The RON receptoris a member of the Met family of cell surface receptor tyrosine kinasesand is primarily expressed on epithelial cells and macrophages. Thebiological response of RON is mediated by binding of its ligand,hepatocyte growth factor-like protein/macrophage stimulating-protein(HGFL). HGFL is primarily synthesized and secreted from hepatocytes asan inactive precursor and is activated at the cell surface. Binding ofHGFL to RON activates RON and leads to the induction of a variety ofintracellular signaling cascades that leads to cellular growth, motilityand invasion. Recent studies have documented RON overexpression in avariety of human cancers including breast, colon, liver, pancreas, andbladder. Moreover, clinical studies have also shown that RONoverexpression is associated with both worse patient outcomes as well asmetastasis. Forced overexpression of RON in transgenic mice leads totumorigenesis in both the lung and the mammary gland and is associatedwith metastatic dissemination. While RON overexpression appears to be ahallmark of many human cancers, the mechanisms by which RON inducestumorigenesis and metastasis are still unclear. Several strategies arecurrently being undertaken to inhibit RON as a potential therapeutictarget; current strategies include the use of RON blocking proteins,small interfering RNA (siRNA), monoclonal antibodies, and small moleculeinhibitors. In total, these data suggest that RON is a critical factorin tumorigenesis and that inhibition of this protein, alone or incombination with current therapies, may prove beneficial in thetreatment of cancer patients.

In addition, TAK1, or CHK2 are valuable targets in immunity and cellulardamage response pathways (Delaney & Mlodzik (2006) Cell Cycle 5(24):2852-5, describing TGF-beta activated kinase-1 and new insights into thediverse roles of TAK1 in development and immunity. A number of recentpublications have examined the role of TAK1 in model systems rangingfrom fly to mouse. Rather than fit into a clearly defined linearmolecular pathway, TAK1 seems to act in a signaling nexus that respondsto a variety of upstream signals, including inflammatory molecules anddevelopmental cues. TAK1 then influences a number of downstreamprocesses ranging from innate immune responses to patterning anddifferentiation via JNK, NFkappaB and TCFbeta-catenin signaling. Thesedifferences in function are not simply a matter of cell type. Forexample, NFkappaB signaling in a particular cell may or may not requireTAK1 depending on the nature of the activating signal. Interestingly,the multi-task functionality of TAK1 is conserved between vertebrate andinvertebrate species. Studies of TAK1 in multiple experimental systemsare likely to reveal more roles for this kinase and also elucidatemechanisms by which other signaling molecules fulfill diverse signalingroles.

Furthermore, the checkpoint kinases, Chk1 and Chk2 are Ser/Thr proteinkinases, which function as key regulatory kinases in cellular DNA damageresponse pathways limiting cell-cycle progression in the presence of DNAdamage. The development of checkpoint kinase inhibitors for thetreatment of cancer has been a major objective in drug discovery overthe past decade, as evidenced by three checkpoint kinase inhibitorsentering clinic trials since late 2005. A large number of chemicallydiverse Chk1 and Chk2 kinase inhibitors have appeared in the recentpatent literature. Common structural motifs of the checkpoint kinaseinhibitors were identified. There are currently three checkpoint kinaseinhibitors in clinical development, a continuing effort by thepharmaceutical industry to identify novel scaffolds for checkpointkinase inhibition (Janetka & Ashwell (2009) Expert Opin Ther Pat. 200919(2): 165-97).

Further prior art documents are as follows:

WO 2000/012497 deals with quinazoline derivatives as medicaments. Theinternational patent application does not disclose [1,8]naphthyridinederivatives.

WO 2000/058307 is directed to [1,8]naphthyridine compounds asneurokinin-3 receptor ligands. However, the substitution pattern of the[1,8]naphthyridine moiety differs from that of the present invention.

WO 2003/097615 relates to the treatment of fibroproliferative disordersusing TGF-beta inhibitors. The international patent application does notdisclose [1,8]naphthyridine derivatives.

WO 2004/010929 describes methods for improvement of lung function usingTGF-beta inhibitors. The international patent application does notdisclose [1,8]naphthyridine derivatives.

WO 2005/065691 is directed to the treatment of malignant gliomas withTGF-beta inhibitors. The international patent application does notdisclose [1,8]naphthyridine derivatives.

US 2006/286408 deals with [1,8]naphthyridine compounds and organiclight-emitting device using the same. However, the substitution patternof the [1,8]naphthyridine moiety differs from that of the presentinvention.

WO 2007/016525 describes pharmaceutical compositions for the preventionand treatment of complex diseases and their delivery by insertablemedical devices. The international patent application does not disclose[1,8]naphthyridine derivatives.

WO 2010/033906 relates to the efficient induction of pluripotent stemcells using small molecule compounds. The international patentapplication does not disclose [1,8]naphthyridine derivatives.

International patent application PCT/EP2010/007743 is directed tohetaryl-[1,8]naphthyridine derivatives as among others TGF-betainhibitors. However, the substitution pattern of the [1,8]naphthyridinemoiety differs from that of the present invention.

The citation of any reference in this application is not an admissionthat the reference is relevant prior art to this application.

DESCRIPTION OF THE INVENTION

The present invention has the object to provide novel [1,8]naphthyridinederivatives.

The object of the present invention has surprisingly been solved in oneaspect by providing compounds of formula (I)

wherein:

-   -   W₁, W₂, W₃, W₄ denotes independently from each other N or CR³,    -   W₅ denotes N or C, preferably denotes N or CR³, more preferably        denotes N,    -   Z denotes C═O, NR⁴, C═N, O, S, CH, N═N or N═O, preferably        denotes C═O, N(R⁴)CO, NR⁴, C═N, O, CON(R⁴), S, CH, N═N or N═C,        more preferably denotes C═O, N(R⁴)CO, NR⁴, C═N, O, CON(R⁴), S,        CH or N═N,    -   R¹ denotes a monocyclic aryl having 5, 6, 7, 8, 9 or 10 C atoms        or a monocyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13        or 14 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, each of        which can be independently substituted by at least one        substituent selected from the group consisting of Y, Hal, CN,        CF₃ or OY,    -   R² denotes H, Hal, A, —(CYY)_(n)—OY, —(CYY)_(n)—NYY,        —(CYY)_(n)-Het, SY, NO₂, CN, COOY, —CO—NYY, —NY—COA, —NY—SO₂A,        —SO₂—NYY, S(O)_(m)A, —CO-Het, —O(CYY)_(n)—OY, —O(CYY)_(n)—NYY,        —O(CYY)_(n)-Het, —NH—COOA, —NH—CO—NYY, —NH—COO—(CYY)_(n)—NYY,        —NH—COO—(CYY)_(n)-Het, —NH—CO—NH—(CYY)_(n)—NYY,        —NH—CO—NH(CYY)_(n)-Het, —OCO—NH—(CYY)_(n)—NYY,        —OCO—NH—(CYY)_(n)-Het, CHO, COA, ═S, ═NY, ═O or a monocyclic        aryl having 5, 6, 7, 8, 9 or 10 C atoms or a monocyclic        heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms        and 1, 2, 3, 4 or 5 N, O and/or S atoms, each of monocyclic aryl        and monocyclic heteroaryl can be independently substituted by at        least one substituent selected from the group consisting of Y,        Hal, CN, CF₃ or OY,    -   R³ denotes H, OY, NYY or NY—COY, preferably denotes H, OY, NYY,        NY—COY, NY—CO—(CYY)_(n)—OY, NY—COY—NYY, NY—(CYY)_(n)—NYY,        O—(CYY)_(n)—NYY or O—(CYY)_(n)-Het,    -   R⁴ denotes H, A, —(CYY)_(o)-Het or —(CYY)_(o)—NYY, preferably        denotes H, A, —(CYY)_(o)-Het, —(CYY)_(o)—NYY or —(CYY)_(o)—OY,    -   R⁵ denotes H, preferably denotes H, A, OY, NYY or Het,    -   Y denotes H or A, preferably in case of —(CYY)_(n/o)—Y        additionally denotes H, A or OH,    -   A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6,        7, 8, 9 or 10 C atoms, in which 1, 2, 3, 4, 5, 6 or 7 H atoms        can be replaced independently from one another by Hal and/or in        which one or two CH₂ groups can be replaced independently of one        another by a O, S, SO, SO₂, a —CY═CY— group and/or a —C≡C—        group; alternatively, A denotes cycloalkyl with 3, 4, 5, 6, 7 or        8 C-atoms,    -   Het denotes a saturated or unsaturated, mono, bi- or tricyclic        heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,        16, 17, 18, 19 or 20 C atoms and 1, 2, 3, 4 or 5 N, O and/or S        atoms, which can be substituted by at least one substituent        selected from the group consisting of Y, Hal, CN, CF₃, OY,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1 or 2,    -   n denotes 0, 1, 2, 3 or 4,    -   o denotes 2, 3 or 4, preferably denotes 0, 1, 2, 3 or 4, more        preferably if Z is NR⁴, o additionally denotes 2, 3 or 4,    -   p denotes 0, 1, 2 or 3,    -   q denotes 0, 1, 2 or 3,

preferably with the proviso that the following compounds disclosed inPCT/EP2010/007743 are excluded:

-   -   (a)        2-(5-chloro-2-fluoro-phenyl)-4-isoquinolin-4-yl-[1,8]naphthyridine,    -   (b)        4-isoquinolin-4-yl-2-(6-methyl-pyridin-2-yl)-[1,8]naphthyridine,    -   (c)        4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,    -   (d)        4-[2-(2,5-difluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,    -   (e)        N-{4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-yl}-acetamide,    -   (f)        2-(2-fluoro-phenyl)-4-[2,7]naphthyridin-4-yl-[1,8]naphthyridine,    -   (g)        5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,    -   (h)        5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridine,    -   (i)        4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) isprovided, with the further proviso that W₅ denotes N and/or Z excludesN═C, i.e. Z denotes C═C, N(R⁴)CO, NR⁴, C═N, O, CON(R⁴), S, CH or N═N,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein Z is selected from the group consistingof:

-   -   (a) C═C, or    -   (b) N(R⁴)CO, or    -   (c) NR⁴, or    -   (d) C═N, or    -   (e) O, or    -   (f) CON(R⁴),        and preferably is C═C,        and the physiologically acceptable salts, solvates,        stereoisomers and tautomers thereof, including mixtures thereof        in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   (a) W₁, W₃, W₄ denote independently from each other CR³, and W₂        denotes N, or    -   (b) W₂, W₃, W₄ denote independently from each other CR³, and W₁        denotes N, or    -   (c) W₁, W₂, W₄ denote independently from each other CR³, and W₃        denotes N, or    -   (d) W₁, W₂, W₃, W₄ denote independently from each other CR³, or    -   (e) W₁, W₃ denote independently from each other CR³, and W₂, W₄        denotes N,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   R¹ denotes phenyl, which can be substituted by at least one        substituent selected from the group consisting of Y, Hal, CN,        CF₃ or OY,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   R² is absent or denotes H, A, Hal, —(CYY)_(n)—OY, NO₂,        —(CYY)_(n)—NYY, —(CYY)_(n)-Het, —O—(CYY)_(n)-Het,        —O—(CYY)_(n)—OY, —O—(CYY)_(n)—NYY, NY—(CYY)_(n)—NYY, NY—COY or a        monocyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14        C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, where the        monocyclic heteroaryl can be independently substituted by at        least one substituent selected from the group consisting of Y,        Hal, CN, CF₃ or OY,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   W₁, W₃, W₄ denote independently from each other CR³, and    -   W₂ denotes N, or    -   W₁, W₂, W₃, W₄ denote independently from each other CR³, or

W₁, W₃, denote independently from each other CR³, and

-   -   W₂, W₄ denote independently from each other N, and    -   Z denotes C═C, NR⁴, C═N, O or N═C, and    -   R¹ denotes phenyl, which can be substituted by at least one        substituent selected from the group consisting of Y, Hal, CN,        CF₃ or OY, and    -   R² is absent or denotes H, A, —(CYY)_(n)—OY, NO₂, —(CYY)_(n)—NYY        or —O(CYY)_(n)-Het,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   W₁, W₃, W₄ denote independently from each other CR³, and    -   W₂, W₅ denote N, and    -   Z denotes C═C, and    -   R¹ denotes phenyl, which can be substituted by at least one        substituent selected from the group consisting of Y, Hal, CN,        CF₃ or OY,

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.

In another aspect, the object of the present invention has surprisinglybeen solved by providing a compound selected from the group consistingof:

Compound 1

2-(5-Chloro-2- fluoro-phenyl)-4- (1H-pyrrolo[2,3- c]pyridin-3-yl)-[1,8]naphthyridine Compound 2

2-(5-Chloro-2- fluoro-phenyl)-4- isoquinolin-5-yl- [1,8]naphthyridineCompound 3

2-(2-Fluoro-5- trifluoromethyl- phenyl)-4-(1H- pyrrolo[2,3-c]pyridin-3-yl)- [1,8]naphthyridine Compound 4

5-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-1-ylamine Compound 5

2-(5-Chloro-2- fluoro-phenyl)-4- [1-(2-methoxy- ethyl)-1H- pyrrolo[2,3-c]pyridin-3-yl]- [1,8]naphthyridine Compound 6

5-[2-(6-Methyl- pyridin-2-yl)- [1,8]naphthyridin- 4-yl]-isoquinolin-1-ylamine Compound 7

2-(6-Methyl- pyridin-2-yl)-4- [2,6]naphthyridin- 1-yl-[1,8]naphthyridine Compound 8

5-[2-(2-Fluoro-5- trifluoromethyl- phenyl)- [1,8]naphthyridin-4-yl]-isoquinolin- 1-ylamine Compound 9

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin- 1-ylamineCompound 10

5-[2-(2,5-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-1-ylamine Compound 11

5-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine Compound 12

2-(5-Chloro-2- fluoro-phenyl)-4- furo[2,3-c]pyridin- 3-yl-[1,8]naphthyridine Compound 13

3-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-furo[2,3-c]pyridin-7- ylamine Compound 14

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-1-ylamine Compound 15

8-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-quinazolin-4- ylamineCompound 16

2-(2-Fluoro- phenyl)-4-(8-nitro- isoquinolin-5-yl)- [1,8]naphthyridineCompound 17

2-(2-Fluoro- phenyl)-4-(8- methoxy- isoquinolin-5-yl)-[1,8]naphthyridine Compound 18

4-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-pyrido[3,4-d]pyrimidine Compound 19

2-(2-Fluoro- phenyl)-4- isoquinolin-5-yl- [1,8]naphthyridine Compound 20

5-[2-(2,5-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine hydrochloride Compound 21

5-[2-(6-Methyl- pyridin-2-yl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine hydrochloride Compound 22

5-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8-ylamine hydrochloride Compound 23

2-(2-Fluoro- phenyl)-4- [2,6]naphthyridin- 1-yl- [1,8]naphthyridineCompound 24

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-pyrido[3,4-d]pyrimidine Compound 25

Compound 26

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-8-methoxy-isoquinolin-1- ylamine Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

2-(5-Chloro-2- fluoro-phenyl)-4- [2,6]naphthyridin- 1-yl-[1,8]naphthyridine Compound 36

8-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-pyrido[3,4-d]pyrimidin-4- ylamine Compound 37

5-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-[1,7]naphthyridine Compound 38

5-[2-(2,5-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8-ylamine Compound 39

2-{5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8-yloxy}-ethanol Compound 40

2-(2-Fluoro- phenyl)-4-(5- methoxy- [2,6]naphthyridin- 1-yl)-[1,8]naphthyridine Compound 41

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin- 8-ylamineCompound 42

4-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,7]naphthyridin-1-ylamine Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-8-methoxy-isoquinolin-3- ylamine Compound 49

5-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-3-ylamine Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

Compound 55

Compound 56

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

Compound 62

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin- 6-ylamineCompound 63

2-(2-Fluoro- phenyl)-4-[8-(2- morpholin-4-yl- ethoxy)-isoquinolin-5-yl]- [1,8]naphthyridine Compound 64

2-(2-Fluoro- phenyl)-4-[5-(1- methyl-1H- pyrazol-4-yl)-isoquinolin-8-yl]- [1,8]naphthyridine Compound 65

2-(2-Fluoro- phenyl)-4-[8-(1- methyl-1H- pyrazol-4-yl)-isoquinolin-5-yl]- [1,8]naphthyridine Compound 66

1-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-3-ylamine Compound 67

4-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2-(2- hydroxy-ethyl)-2H- [2,7]naphthyridin- 1-one Compound 68

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-hydroxy-ethyl)- [2,7]naphthyridin- 1-one Compound 69

N-{5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-1-yl}-acetamide Compound 70

2-(2-Fluoro- phenyl)-4-(6- methoxy- isoquinolin-5-yl)-[1,8]naphthyridine Compound 71

2-Dimethylamino- N-{5-[2-(2-fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-yl}-acetamide Compound 72

4-[2-(2,5-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-hydroxy-ethyl)- 2H- [2,7]naphthyridin- 1-one Compound 73

N-{5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-1-yl}-2-methoxy- acetamide Compound 74

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-methyl-2H-[2,7]naphthyridin- 1-one Compound 75

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(3-hydroxy-propyl)- 2H- [2,7]naphthyridin- 1-one Compound 76

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-morpholin-4-yl- ethyl)-2H- [2,7]naphthyridin- 1-one Compound 77

2-(5-Chloro-2- fluoro-phenyl)-4- [1-(2-morpholin-4- yl-ethoxy)-[2,7]naphthyridin- 4-yl]- [1,8]naphthyridine Compound 78

2-(2-Fluoro- phenyl)-4-[1-(2- morpholin-4-yl- ethoxy)-[2,7]naphthyridin- 4-yl]- [1,8]naphthyridine Compound 79

2-{1-Amino-5-[2- (2-fluoro-phenyl)- [1,8]naphthyridin-4-yl]-isoquinolin- 8-yloxy}-ethanol Compound 80

5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2H- [2,6]naphthyridin-1-one Compound 81

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2,3-dihydroxy-propyl)- 2H- [2,7]naphthyridin- 1-one Compound 82

(2-{5-[2-(5- Chloro-2-fluoro- phenyl)- [1,8]naphthyridin-4-yl]-isoquinolin- 8-yloxy}-ethyl)- dimethyl-amine Compound 83

2-(5-Chloro-2- fluoro-phenyl)-4- (8-chloro- isoquinolin-5-yl)-[1,8]naphthyridine Compound 84

5-[2-(5-Methyl- furan-2-yl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine Compound 85

N-{5-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-6-yl}-acetamide Compound 86

(2-{5-[2-(5- Chloro-2-fluoro- phenyl)- [1,8]naphthyridin-4-yl]-isoquinolin- 8-yloxy}-ethyl)- diethyl-amine Compound 87

5-(2-Phenyl- [1,8]naphthyridin- 4-yl)- [2,6]naphthyridin- 1-ylamineCompound 88

2-(2-Fluoro- phenyl)-4-(6-oxy- [2,6]naphthyridin- 1-yl)-[1,8]naphthyridine Compound 89

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2H-[2,7]naphthyridin- 1-one Compound 90

5-[2-(2-Chloro- phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-1-ylamine Compound 91

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-pyrrolidin-1-yl- ethyl)-2H- [2,7]naphthyridin- 1-one Compound 92

N′-{5-[2-(5- Chloro-2-fluoro- phenyl)- [1,8]naphthyridin-4-yl]-isoquinolin- 8-yl}-N,N-diethyl- ethane-1,2- diamine Compound 93

2-Phenyl-4-(1H- pyrrolo[2,3- b]pyridin-3-yl)- [1,8]naphthyridineCompound 94

2-(2,6-Dimethoxy- phenyl)-4-(1H- pyrrolo[2,3- b]pyridin-3-yl)-[1,8]naphthyridine Compound 95

4-(1H-Pyrrolo[2,3- b]pyridin-3-yl)-2- (3-trifluoromethyl- phenyl)-[1,8]naphthyridine Compound 96

2-(2-Fluoro-5- trifluoromethyl- phenyl)-4-(1H- pyrrolo[2,3-b]pyridin-3-yl)- [1,8]naphthyridine Compound 97

2-(4-Fluoro-2- methyl-phenyl)-4- (1H-pyrrolo[2,3- b]pyridin-3-yl)-[1,8]naphthyridine Compound 98

(2-{4-[2-(5- Chloro-2-fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-[2,7]naphthyridin- 1-yloxy}-ethyl)- diethyl-amine Compound 99

2-(2,5-Difluoro- phenyl)-4-(8- methoxy- isoquinolin-5-yl)-[1,8]naphthyridine Compound 100

2-(5-Chloro-2- fluoro-phenyl)-4- [1-(2-pyrrolidin-1- yl-ethoxy)-[2,7]naphthyridin- 4-yl]- [1,8]naphthyridine Compound 101

2-Furan-2-yl-4- (1H-pyrrolo[2,3- c]pyridin-3-yl)- [1,8]naphthyridineCompound 102

2-(5-Chloro-2- fluoro-phenyl)-4- [8-(2-pyrrolidin-1- yl-ethoxy)-isoquinolin-5-yl]- [1,8]naphthyridine Compound 103

(2-{5-[2-(2,5- Difluoro-phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8-yloxy}-ethyl)- diethyl-amine Compound 104

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-diethylamino- ethyl)-2H- [2,7]naphthyridin- 1-one Compound 105

4-(1H-Pyrrolo[2,3- b]pyridin-3-yl)-2- (4-trifluoromethyl- phenyl)-[1,8]naphthyridine Compound 106

1-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-4-methoxy- pyrido[3,4-d]pyridazine Compound 107

4-[2-(2,5-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2H-[2,7]naphthyridin- 1-one Compound 108

2-(2-Methyl-furan- 3-yl)-4-(1H- pyrrolo[2,3- c]pyridin-3-yl)-[1,8]naphthyridine Compound 109

5-[2-(2,6-Difluoro- phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine Compound 110

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-1-(2-morpholin-4-yl- ethyl)-1H- [1,7]naphthyridin- 2-one Compound 111

4-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [1,7]naphthyridineCompound 112

4-[2-(5-Chloro-2- fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-morpholin-4-yl- ethoxy)- [1,7]naphthyridine Compound 113

4-[2-(2-Fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- [1,7]naphthyridin-8-ylamine Compound 114

5-(5-Amino- [2,6]naphthyridin- 1-yl)-7-(2-fluoro- phenyl)-[1,8]naphthyridin- 2-ylamine Compound 115

2-(2-Fluoro- phenyl)-4-(4- methoxy- [2,6]naphthyridin- 1-yl)-[1,8]naphthyridine Compound 116

5-[2-(2-Fluoro- phenyl)-6-(1- methyl-1H- pyrazol-4-yl)-[1,8]naphthyridin- 4-yl]- [2,6]naphthyridin- 1-ylamine Compound 117

5-(1-Amino- isoquinolin-5-yl)- 7-(2-fluoro- phenyl)- [1,8]naphthyridin-2-ylamine Compound 118

2-(3-Methyl- pyrazol-1-yl)-4- (1H-pyrrolo[2,3- c]pyridin-3-yl)-[1,8]naphthyridine Compound 119

4-Isoquinolin-5-yl- 2-(2-methyl-furan- 3-yl)- [1,8]naphthyridineCompound 120

2-(2-Fluoro- phenyl)-4-(5H- pyrrolo[2,3- b]pyrazin-7-yl)-[1,8]naphthyridine

and the physiologically acceptable salts, solvates, stereoisomers and

tautomers thereof, including mixtures thereof in all ratios.

For the avoidance of doubt, if chemical name and chemical structure ofthe above illustrated compounds do not correspond by mistake, thechemical structure is regarded to unambigously define the compound.

All the above generically or explicitly disclosed compounds, includingpreferred subsets/embodiments of the herein disclosed formula (I) andCompounds 1 to 120, are hereinafter referred to as compounds of the(present) invention.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC organisation for chemical compounds and especially organiccompounds.

The terms indicated for explanation of the above compounds of theinvention always, unless indicated otherwise in the description or inthe claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents.

The term “substituted” means that the corresponding radical, group ormoiety has one or more substituents. Where a radical has a plurality ofsubstituents, and a selection of various substituents is specified, thesubstituents are selected independently of one another and do not needto be identical.

The terms “alkyl” or “A” as well as other groups having the prefix “alk”for the purposes of this invention refer to acyclic saturated orunsaturated hydrocarbon radicals which may be branched or straight-chainand preferably have 1 to 10 carbon atoms, i.e. C₁-C₁₀-alkanyls,C₂-C₁₀-alkenyls and C₂-C₁₀-alkynyls. Alkenyls have at least one C—Cdouble bond and alkynyls at least one C—C triple bond. Alkynyls mayadditionally also have at least one C—C double bond. Examples ofsuitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl,tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl,n-hexadecyl, n-octadecyl, n-icosanyl, n-docosanyl, ethylenyl(vinyl),propenyl (—CH₂CH═CH₂; —CH═CH—CH₃, —C(═CH₂)—CH₃), butenyl, pentenyl,hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl,icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13-enyl,(Z)-docos-13-enyl, ethynyl, propynyl (—CH₂—C≡CH, —C≡C—CH₃), butynyl,pentynyl, hexynyl, heptynyl, octynyl. Especially preferred isC₁-₄-alkyl. A C₁-₄-alkyl radical is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl.

The term “cycloalkyl” for the purposes of this invention refers tosaturated and partially unsaturated non-aromatic cyclic hydrocarbongroups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3to 12, most preferably 3 to 8 carbon atoms. The cycloalkyl radical mayalso be part of a bi- or polycyclic system, where, for example, thecycloalkyl radical is fused to an aryl, heteroaryl or heterocyclylradical as defined herein by any possible and desired ring member(s).The bonding to the compounds of the general formula can be effected viaany possible ring member of the cycloalkyl radical. Examples of suitablecycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl,cyclopentenyl and cyclooctadienyl. Especially preferred areC₃-C₉-cycloalkyl and C₄- C₈-cycloalkyl. A C₄-C₈-cycloalkyl radical isfor example a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl.

The term “heterocyclyl” or “heterocycle” for the purposes of thisinvention refers to a mono- or polycyclic system of 3 to 20, preferably5 or 6 to 14 ring atoms comprising carbon atoms and 1, 2, 3, 4, or 5heteroatoms, in particular nitrogen, oxygen and/or sulfur which areidentical or different. The cyclic system may be saturated, mono- orpolyunsaturated but may not be aromatic. In the case of a cyclic systemconsisting of at least two rings the rings may be fused or spiro- orotherwise connected. Such “heterocyclyl” radicals can be linked via anyring member. The term “heterocyclyl” also includes systems in which theheterocycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the heterocycle isfused to an “aryl”, “cycloalkyl”, “heteroaryl” or “heterocyclyl” groupas defined herein via any desired and possible ring member of theheterocycyl radical. The bonding to the compounds of the general formulacan be effected via any possible ring member of the heterocycyl radical.Examples of suitable “heterocyclyl” radicals are pyrrolidinyl,thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl,thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl,dihydropyranyl, indolinyl, indolinylmethyl, imidazolidinyl,2-aza-bicyclo[2.2.2]octanyl.

The term “aryl” for the purposes of this invention refers to a mono- orpolycyclic aromatic hydrocarbon systems having 3 to 14, preferably 5 to14, more preferably 5 to 10 carbon atoms. The term “aryl” also includessystems in which the aromatic cycle is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, such as wherethe aromatic cycle is fused to an “aryl”, “cycloalkyl”, “heteroaryl” or“heterocyclyl” group as defined herein via any desired and possible ringmember of the aryl radical. The bonding to the compounds of the generalformula can be effected via any possible ring member of the arylradical. Examples of suitable “aryl” radicals are phenyl, biphenyl,naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl,indenyl, or 1,2,3,4-tetrahydronaphthyl. The most preferred aryl isphenyl.

The term “heteroaryl” for the purposes of this invention refers to a 3to 15, preferably 5 to 14, more preferably 5-, 6- or 7-membered mono- orpolycyclic aromatic hydrocarbon radical which comprises at least 1,where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen,oxygen and/or sulfur, where the heteroatoms are identical or different.The number of nitrogen atoms is preferably 0, 1, 2, or 3, and that ofthe oxygen and sulfur atoms is independently 0 or 1. The term“heteroaryl” also includes systems in which the aromatic cycle is partof a bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the aromatic cycle is fused to an “aryl”,“cycloalkyl”, “heteroaryl” or “heterocyclyl” group as defined herein viaany desired and possible ring member of the heteroaryl radical. Thebonding to the compounds of the general formula can be effected via anypossible ring member of the heteroaryl radical. Examples of suitable“heteroaryl” are acridinyl, benzdioxinyl, benzimidazolyl,benzisoxazolyl, benzodioxolyl, benzofuranyl, benzothiadiazolyl,benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, cinnolinyl,dibenzofuranyl, dihydrobenzothienyl, furanyl, furazanyl, furyl,imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl,isobenzylfuranyl, isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinolyl, quinoxalinyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazinyl,triazolyl.

For the purposes of the present invention, the terms “alkyl-cycloalkyl”,“cycloalkylalkyl”, “alkyl-heterocyclyl”, “heterocyclylalkyl”,“alkyl-aryl”, “arylalkyl”, “alkyl-heteroaryl” and “heteroarylalkyl” meanthat alkyl, cycloalkyl, heterocycl, aryl and heteroaryl are each asdefined above, and the cycloalkyl, heterocyclyl, aryl and heteroarylradical is bonded to the compounds of the general formula via an alkylradical, preferably C₁-C₈-alkyl radical, more preferably C₁-C₄-alkylradical.

The term “alkyloxy” or “alkoxy” for the purposes of this inventionrefers to an alkyl radical according to above definition that isattached to an oxygen atom. The attachment to the compounds of thegeneral formula is via the oxygen atom. Examples are methoxy, ethoxy andn-propyloxy, propoxy, isopropoxy. Preferred is “C₁-C₄-alkyloxy” havingthe indicated number of carbon atoms.

The term “cycloalkyloxy” or “cycloalkoxy” for the purposes of thisinvention refers to a cycloalkyl radical according to above definitionthat is attached to an oxygen atom. The attachment to the compounds ofthe general formula is via the oxygen atom. Examples are cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclooctyloxy. Preferred is “C₃-C₉cycloalkyloxy” having the indicatednumber of carbon atoms.

The term “heterocyclyloxy” for the purposes of this invention refers toa heterocyclyl radical according to above definition that is attached toan oxygen atom. The attachment to the compounds of the general formulaeis via the oxygen atom. Examples are pyrrolidinyloxy,thiapyrrolidinyloxy, piperidinyloxy, piperazinyloxy.

The term “aryloxy” for the purposes of this invention refers to an arylradical according to above definition that is attached to an oxygenatom. The attachment to the compounds of the general formula is via theoxygen atom. Examples are phenyloxy, 2-naphthyloxy, 1-naphthyloxy,biphenyloxy, indanyloxy. Preferred is phenyloxy.

The term “heteroaryloxy” for the purposes of this invention refers to aheteroaryl radical according to above definition that is attached to anoxygen atom. The attachment to the compounds of the general formula isvia the oxygen atom. Examples are pyrrolyloxy, thienyloxy, furyloxy,imidazolyloxy, thiazolyloxy.

The term “carbonyl” or “carbonyl moiety” for the purposes of thisinvention refers to a —C(O)— group.

The term “alkylcarbonyl” for the purposes of this invention refers to a“alkyl-C(O)—” group, wherein alkyl is as defined herein.

The term “alkoxycarbonyl” or “alkyloxycarbonyl” for the purposes of thisinvention refers to a “alkyl-O—C(O)—” group, wherein alkyl is as definedherein.

The term “alkoxyalkyl” for the purposes of this invention refers to a“alkyl-O— alkyl-” group, wherein alkyl is as defined herein.

The term “haloalkyl” for the purposes of this invention refers to analkyl group as defined herein comprising at least one carbon atomsubstituent with at least one halogen as defined herein.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro), or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine.“Halogen” preferably means a fluorine, chlorine or bromine atom.Fluorine is most preferred, when the halogens are substituted on analkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).

The term “hydroxyl” or “hydroxy” means an OH group.

The term “composition”, as in pharmaceutical composition, for thepurposes of this invention is intended to encompass a product comprisingthe active ingredient(s), and the inert ingredient(s) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

The terms “administration ^(of) and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individualist need.

As used herein, the term “effective amount” refers to any amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

All stereoisomers of the compounds of the invention are contemplated,either in a mixture or in pure or substantially pure form. The compoundsof the invention can have asymmetric centers at any of the carbon atoms.Consequently, they can exist in the form of their racemates, in the formof the pure enantiomers and/or diastereomers or in the form of mixturesof these enantiomers and/or diastereomers. The mixtures may have anydesired mixing ratio of the stereoisomers.

Thus, for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor nonchiral phases or by recrystallization from an optionally opticallyactive solvent or with use of an optically active acid or base or byderivatization with an optically active reagent such as, for example, anoptically active alcohol, and subsequent elimination of the radical.

The compounds of the invention may be present in the form of theirdouble bond isomers as “pure” E or Z isomers, or in the form of mixturesof these double bond isomers.

Where possible, the compounds of the invention may be in the form of thetautomers, such as keto-enol tautomers.

It is likewise possible for the compounds of the invention to be in theform of any desired prodrugs such as, for example, esters, carbonates,carbamates, ureas, amides or phosphates, in which cases the actuallybiologically active form is released only through metabolism. Anycompound that can be converted in vivo to provide the bioactive agent(i.e. compounds of the invention) is a prodrug within the scope andspirit of the invention.

Various forms of prodrugs are well known in the art and are describedfor instance in:

(i) Wermuth C G et al., Chapter 31: 671-696, The Practice of MedicinalChemistry, Academic Press 1996;

(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and

(iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design andDevelopment, Harwood Academic Publishers 1991.

Said references are incorporated herein by reference.

It is further known that chemical substances are converted in the bodyinto metabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.

Any biologically active compound that was converted in vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

The compounds of the invention can, if they have a sufficiently basicgroup such as, for example, a secondary or tertiary amine, be convertedwith inorganic and organic acids into salts. The pharmaceuticallyacceptable salts of the compounds of the invention are preferably formedwith hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid,racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid,lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid,glutamic acid or aspartic acid. The salts which are formed are, interalia, hydrochlorides, chlorides, hydrobromides, bromides, iodides,sulfates, phosphates, methanesulfonates, tosylates, carbonates,bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates,malonates, maleates, succinates, tartrates, malates, embonates,mandelates, fumarates, lactates, citrates, glutarates, stearates,aspartates and glutamates. The stoichiometry of the salts formed fromthe compounds of the invention may moreover be an integral ornon-integral multiple of one.

The compounds of the invention can, if they contain a sufficientlyacidic group such as, for example, the carboxy, sulfonic acid,phosphoric acid or a phenolic group, be converted with inorganic andorganic bases into their physiologically tolerated salts. Examples ofsuitable inorganic bases are ammonium, sodium hydroxide, potassiumhydroxide, calcium hydroxide, and of organic bases are ethanolamine,diethanolamine, triethanolamine, ethylenediamine, t-butylamine,t-octylamine, dehydroabietylamine, cyclohexylamine,dibenzylethylene-diamine and lysine. The stoichiometry of the saltsformed from the compounds of the invention can moreover be an integralor non-integral multiple of one.

It is likewise possible for the compounds of the invention to be in theform of their solvates and, in particular, hydrates which can beobtained for example by crystallization from a solvent or from aqueoussolution. It is moreover possible for one, two, three or any number ofsolvate or water molecules to combine with the compounds of theinvention to give solvates and hydrates.

By the term “solvate” is meant a hydrate, an alcoholate, or othersolvate of crystallization.

It is known that chemical substances form solids which exist indifferent order states which are referred to as polymorphic forms ormodifications. The various modifications of a polymorphic substance maydiffer greatly in their physical properties. The compounds of theinvention can exist in various polymorphic forms and certainmodifications may moreover be metastable. All these polymorphic forms ofthe compounds are to be regarded as belonging to the invention.

The compounds of the invention are surprisingly characterized by astrong and/or selective inhibition of ATP consuming proteins, preferablytyrosine kinases and serine/threonine kinases, more preferably TGF-beta,RON, TAK1, CHK2, PDK1, Met, PKD1, MINK1, SAPK2-alpha, SAPK2-beta, MKK1,GCK, HER4, ALK1, ALK2, ALK4, ALK5 and TbR type II. It is more preferredto inhibit serine/threonine kinases. Most preferred kinases to beinhibited are TGF-beta receptor kinase, RON, TAK1, PKD1, MINK1,SAPK2-alpha, SAPK2-beta and/or CHK2, highly preferably TGF-beta receptorkinase.

Due to their surprisingly strong and/or selective enzyme inhibition, thecompounds of the invention can be advantageously administered at lowerdoses compared to other less potent or selective inhibitors of the priorart while still achieving equivalent or even superior desired biologicaleffects. In addition, such a dose reduction may advantageously lead toless or even no medicinal adverse effects. Further, the high inhibitionselectivity of the compounds of the invention may translate into adecrease of undesired side effects on its own regardless of the doseapplied.

The compounds of the invention being ATP consuming protein inhibitorsgenerally have an inhibition constant IC₅₀ of less than about 10 μM, andpreferably less than about 1 μM.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated inenzyme-based assays, for example assays as described herein. In suchenzyme-based assays, the compounds according to the invention preferablyexhibit and cause an inhibiting effect, which is usually documented byIC₅₀ values in a suitable range, preferably in the micromolar range andmore preferably in the nanomolar range.

As discussed herein, these signaling pathways are relevant for variousdiseases. Accordingly, the compounds according to the invention areuseful in the prophylaxis and/or treatment of diseases that aredependent on the said signaling pathways by interaction with one or moreof the said signaling pathways. The present invention therefore relatesto compounds according to the invention as promoters or inhibitors,preferably as inhibitors, of the signaling pathways described herein,particularly the TGF-β signaling pathway.

The object of the present invention has surprisingly been solved inanother aspect by providing the use of a compound of the invention forinhibiting ATP consuming proteins, preferably TGF-beta receptor kinase,RON, TAK1, PKD1, MINK1, SAPK2-alpha, SAPK2-beta and/or CHK2.

The terms “inhibiting, inhibition and/or retardation” are intended torefer for the purposes of the present invention to as follows: “partialor complete inhibiting, inhibition and/or retardation”. In this case, itis within the specialist knowledge of the average person skilled in theart to measure and determine such inhibiting, inhibition, and/orretardation by means of the usual methods of measurement anddetermination. Thus, a partial inhibiting, inhibition and/orretardation, for example, can be measured and determined in relation toa complete inhibiting, inhibition and/or retardation.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing a compound ofthe invention, comprising the steps of:

-   -   (a) reacting a compound of formula (II)

-   -   wherein    -   R⁶ denotes Hal or B(OH)₂, and    -   R¹, R⁵, q and Hal have the meaning as defined above,    -   with a compound of formula (III)

-   -   wherein    -   R⁷ denotes Hal, boronic acid or a ester of boronic acid, and    -   R², p, Z, W₁, W₂, W₃, W₄, W₅ and Hal have the meaning as defined        above,    -   to yield the compound of formula (I)

-   -   wherein    -   R¹, R², R⁵, p, q, Z, W₁, W₂, W₃, W₄, and W₅ have the meaning as        defined above,    -   or    -   b) reacting a compound of formula (IV)

-   -   wherein    -   R¹, R², R⁵, p, q, Z, W₁, W₃, W₄, and W₅ have the meaning as        defined above, with alkyl- or arylsulfonylchloride, such as        methanesulfonylchloride or p-toluenesulfonylchloride, pyridine        or alkyl-pyridine and a primary alkylamine, such as        ethanolamine, propylamine or butylamine,    -   to yield the compound of formula (I′) and/or (I″)

-   -   wherein    -   R¹, R², R⁵, p, q, Z, W₁, W₃, W₄, and W₅ have the meaning as        defined above and for formula (I′) W₁ is CR³ with R³ being NYY        and Y being H and W₂ is N and for formula (I″) W₃ is CR³ with R³        being NYY and Y being H and W₂ is N,    -   and optionally    -   (c) converting a base or an acid of the compound of formula (I),        (I′) or (I″) into a salt thereof.

Some crude products were subjected to standard chromatography usingsolvent mixtures containing methanol, ethanol, isopropanol, n-hexane,cyclohexane, dichloromethane, n-heptane or petrol ether, respectively.

For a further detailed description of the manufacturing processes,please refer also to the examples and the following general descriptionof the preferred conditions.

A physiologically acceptable salt of a compound of the invention canalso be obtained by isolating and/or treating the compound of theinvention obtained by the described reaction with an acid or a base.

The compounds of the invention and also the starting materials for theirpreparation are, are prepared by methods as described in the examples orby methods known per se, as described in the literature (for example instandard works, such as Houben-Weyl, Methoden der Organischen Chemie[Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; OrganicReactions, John Wiley & Sons, Inc., New York), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials for the claimed process may, if desired, also beformed in situ by not isolating them from the reaction mixture, butinstead immediately converting them further into the compounds of theinvention. On the other hand, it is possible to carry out the reactionstepwise.

Preferably, the reaction of the compounds is carried out in the presenceof a suitable solvent, which is preferably inert under the respectivereaction conditions. Examples of suitable solvents are hydrocarbons,such as hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichlorethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents ormixtures with water. Polar solvents are in general preferred. Examplesfor suitable polar solvents are chlorinated hydrocarbons, alcohols,glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. Morepreferred are amides, especially dimethylformamide (DMF).

As stated above, the reaction temperature is between about −100° C. and300° C., depending on the reaction step and the conditions used.

Reaction times are generally in the range between some minutes andseveral days, depending on the reactivity of the respective compoundsand the respective reaction conditions. Suitable reaction times arereadily determinable by methods known in the art, for example reactionmonitoring. Based on the reaction temperatures given above, suitablereaction times generally lie in the range between 10 min and 48 hrs.

A base of a compound of the invention can be converted into theassociated acid-addition salt using an acid, for example by reaction ofequivalent amounts of the base and the acid in a preferably inertsolvent, such as ethanol, followed by evaporation. Suitable acids forthis reaction are, in particular, those which give physiologicallyacceptable salts. Thus, it is possible to use inorganic acids, forexample sulfuric acid, sulfurous acid, dithionic acid, nitric acid,hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as, for example, orthophosphoric acid, sulfamicacid, furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, hexanoic acid, octanoic acid, decanoic acid,hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylicacid, p-toluenesulfonic acid, glycolic acid, embonic acid,chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline,glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid,cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and-disulfonic acids or laurylsulfuric acid.

Salts with physiologically unacceptable acids, for example picrates, canbe used to isolate and/or purify the compounds of the invention.

On the other hand, compounds of the invention can be converted into thecorresponding metal salts, in particular alkali metal salts or alkalineearth metal salts, or into the corresponding ammonium salts, using bases(for example sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Suitable salts are furthermore substitutedammonium salts, for example the dimethyl-, diethyl- anddiisopropylammonium salts, monoethanol-, diethanol- anddiisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts,dibenzylethylenediammonium salts, furthermore, for example, salts witharginine or lysine.

If desired, the free bases of the compounds of the invention can beliberated from their salts by treatment with strong bases, such assodium hydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate, so long as no further acidic groups are present in themolecule. In the cases where the compounds of the invention have freeacid groups, salt formation can likewise be achieved by treatment withbases. Suitable bases are alkali metal hydroxides, alkaline earth metalhydroxides or organic bases in the form of primary, secondary ortertiary amines.

Every reaction step described herein can optionally be followed by oneor more working up procedures and/or isolating procedures. Suitable suchprocedures are known in the art, for example from standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Examples for suchprocedures include, but are not limited to evaporating a solvent,distilling, crystallization, fractionised crystallization, extractionprocedures, washing procedures, digesting procedures, filtrationprocedures, chromatography, chromatography by HPLC and dryingprocedures, especially drying procedures in vacuo and/or elevatedtemperature.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention for use in the treatment and/or prophylaxis ofphysiological and/or pathophysiological conditions selected from thegroup consisting of: “cancer, tumour, malignant tumours, benign tumours,solid tumours, sarcomas, carcinomas, hyperproliferative disorders,carcinoids, Ewing sarcomas, Kaposi sarcomas, brain tumours, tumoursoriginating from the brain and/or the nervous system and/or themeninges, gliomas, glioblastomas, neuroblastomas, stomach cancer, kidneycancer, kidney cell carcinomas, prostate cancer, prostate carcinomas,connective tissue tumours, soft tissue sarcomas, pancreas tumours, livertumours, head tumours, neck tumours, laryngeal cancer, oesophagealcancer, thyroid cancer, osteosarcomas, retinoblastomas, thymoma,testicular cancer, lung cancer, lung adenocarcinoma, small cell lungcarcinoma, bronchial carcinomas, breast cancer, mamma carcinomas,intestinal cancer, colorectal tumours, colon carcinomas, rectumcarcinomas, gynaecological tumours, ovary tumours/ovarian tumours,uterine cancer, cervical cancer, cervix carcinomas, cancer of body ofuterus, corpus carcinomas, endometrial carcinomas, urinary bladdercancer, urogenital tract cancer, bladder cancer, skin cancer, epithelialtumours, squamous epithelial carcinoma, basaliomas, spinaliomas,melanomas, intraocular melanomas, leukaemias, monocyte leukaemia,chronic leukaemias, chronic myelotic leukaemia, chronic lymphaticleukemia, acute leukaemias, acute myelotic leukaemia, acute lymphaticleukemia, lymphomas, opthalmic diseases, choroidal neovascularization,diabetic retinopathy, inflammatory diseases, arthritis,neurodegeneration, transplant rejection, metastatic growth, fibrosis,restenosis, HIV infection, atherosclerosis, inflammation and disordersof wound healing, angiogenesis, cardiovascular system, bone, CNS and/orPNS.” A corresponding use for the preparation of a medicament for thetreatment and/or prophylaxis of the aforementioned conditions isintended to be comprised. A corresponding method of treatmentadministering at least one compound of the invention to a patient inneed thereof is also intended to be comprised.

Compounds of the invention may be used in combination with one or moreother active substances (ingredients, drugs) in the treatment,prevention, suppression or amelioration of diseases or conditions forwhich compounds of the invention or the other substances have utility.Typically the combination of the drugs is safer or more effective thaneither drug alone, or the combination is safer or more effective thanwould it be expected based on the additive properties of the individualdrugs. Such other drug(s) may be administered, by a route and in anamount commonly used contemporaneously or sequentially with a compoundof the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a combination productcontaining such other drug(s) and the compound of the invention ispreferred. However, combination therapy also includes therapies in whichthe compound of the invention and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the compound ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of the invention.

Examples of other active substances (ingredients, drugs) that may beadministered in combination with a compound of the invention, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to the compounds classes and specificcompounds listed in Table 1:

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfaneProcarbazine Ifosfamide Altretamine Melphalane EstramustinphosphateHexamethylmelamine Mechlorethamine Thiotepa Streptozocine ChlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(AeternaZentaris) Carboxyphthalatoplatinum Satraplatin (JohnsonTetraplatin Matthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Roche)SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycine 5-FluoruracilFludarabine Floxuridine Pentostatine 2-Chlordesoxyadenosine Raltitrexede6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluordesoxycytidine Irofulven(MGI Pharma) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthinylcytidine (Taiho) Topoisomerase Amsacrine Rubitecane (SuperGen)inhibitors Epirubicine Exatecanmesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or Mitoxantrone Gimatecane (Sigma-Tau)Irinotecane (CPT-11) Diflomotecane (Beaufour- 7-Ethyl-10- Ipsen)hydroxycamptothecine TAS-103 (Taiho) Topotecane Elsamitrucine (Spectrum)Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone(Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin-Analogue CKD-602(Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576(Novuspharrna) Antitumor antibiotics Dactinomycin (Actinomycin AmonafideD) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole DeoxyrubicinOxantrazole Valrubicin Losoxantrone Daunorubicin (Daunomycin)Bleomycinsulfate (Blenoxan) Epirubicin Bleomycinacid TherarubicinBleomycin A Idarubicin Bleomycin B Rubidazone Mitomycin C PlicamycinpMEN-10755 (Menarini) Porfiromycin GPX-100 (GemCyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron (Novantron)Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline)Colchicin E7010 (Abbott) Vinblastine PG-TXL (Cell Therapeutics)Vincristine IDN 5109 (Bayer) Vinorelbine A 105972 (Abbott) Vindesine A204197 (Abbott) Dolastatine 10 (NCI) LU 223651 (BASF) Rhizoxine(Fujisawa) D 24851 (ASTA Medica) Mivobuline (Warner-Lambert) ER-86526(Eisai) Cemadotine (BASF) Combretastatine A4 (BMS) RPR 109881A (Aventis)Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B(Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatine PE(Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS 188797(BMS) Dolastatin-10 (NrH) Taxoprexine (Protarga) CA-4 (OXiGENE)Aromatase Aminoglutethimide Exemestane inhibitors Letrozole Atamestane(BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestaneThymidylatesynthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedine (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-Benzylguanine (Paligent)Thymectacine (NewBiotics) Edotreotide (Novartis) FarnesyltransferaseArglabine (NuOncology Labs) Tipifarnibe (Johnson & inhibitorsIonafarnibe (Schering- Johnson) Plough) Perillylalcohol (DOR BAY-43-9006(Bayer) BioPharma) Pump inhibitors CBT-1 (CBA Pharma)Zosuquidar-Trihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209(Schering AG) Biricodar-Dicitrate (Vertex) HistoneacetyltransferaseTacedinaline (Pfizer) Pivaloyloxymethylbutyrate inhibitors SAHA (AtonPharma) (Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT-3 (CollaGenex) inhibitors/Laboratories) BMS-275291 (Celltech) Ribonucleosidereduktase Marimastat(British Biotech) Tezacitabine (Aventis) inhibitors Galliummaltolate(Titan) Didox (Molecules for Health) Triapine (Vion) TNF-alpha agonists/Virulizine (Lorus Revimide (Celgene) antagonists Therapeutics) CDC-394(Celgene) Endotheline-A Atrasentane (Abbot) YM-598 (Yamanouchi) receptorZD-4054 (AstraZeneca) antagonists Retinoic acid Fenretinide (Johnson &Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarzinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Noreline (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccine (CTL 13-Alethine (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and anti-Estrogens Prednisone hormonal agents Conjugated EstrogensMethylprednisolone Ethinylestradiole Prednisolone ChlorotrianisenAminoglutethimide Idenestrole Leuprolide HydroxyprogesteroncaproateGoserelin Medroxyprogesterone Leuporelin Testosterone CetrorelixTestosteronpropionate Bicalutamide Fluoxymesterone FlutamideMethyltestosterone Octreotide Diethylstilbestrole Nilutamide MegestroleMitotane Tamoxifen P-04 (Novogen) Toremofine 2-MethoxyestradiolDexamethasone (EntreMed) Arzoxifen (Eli Lilly) Photodynamic Talaporfine(Light Sciences) Pd-Bacteriopheophorbide agents Theralux(Theratechnologies) (Yeda) Motexafin Gadolinium Lutetium-Texaphyrine(Pharmacyclics) (Pharmacyclics) Hypericine Tyrosinkinase Imatinib(Novartis) Kahalid F (PharmaMar) inhibitors Leflunomid CEP-701(Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca)MLN518 (Millenium) Erlotinib (Oncogene Science) PKC412 (Novartis)Canertjnib (Pfizer) Phenoxodiol O Squalamin (Genaera) Trastuzumab(Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668 (Pharmacia) rhu-Mab(Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex) ZD6474 (AstraZeneca)2C4 (Genentech) Vatalanib (Novartis) MDX-447 (Medarex) PKI166 (Novartis)ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline) IMC-1C11 (ImClone) EKB-509(Wyeth) EKB-569 (Wyeth) Different agents SR-27897 (CCK-A inhibitor,BCX-1777 (PNP inhibitor, Sanofi-Synthelabo) BioCryst) Tocladesine(cyclic-AMP Ranpirnase (Ribonuclease agonist, Ribapharm) stimulans,Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventis)inhibitor, Dong-A) CV-247 (COX-2-Inhibitor, Ivy Tirapazamin (reducingagent, Medical) SRI International) P54 (COX-2 inhibitor, N-Acetylcystein(reducing Phytopharm) agent, Zambon) CapCell ™ (CYP450 R-Flurbiprofen(NF-kappaB stimulans, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3antagonist, 3CPA (NF-kappaB inhibitor, GlycoGenesys) Active Biotech)G17DT immunogen (Gastrin Seocalcitol (Vitamin-D inhibitor, Aphton)receptor agonist, Leo) Efaproxiral (Oxygenator, 131-I-TM-601 (DNA AllosTherapeutics) antagonist, TransMolecular) PI-88 (Heparanase inhibitor,Eflornithin (ODC inhibitor, Progen) ILEX Oncology) Tesmilifen (HistamineMinodronic acid (Osteoclasts antagonist, YM BioSciences) inhibitor,Yamanouchi) Histamine (Histamine-H2 Indisulam (p53 stimulans, receptoragonist, Maxim) Eisai) Tiazofurin (IMPDH inhibitor, Aplidin (PPTinhibitor, Ribapharm) PharmaMar) Cilengitide (Integrine Rituximab (CD20antibody, antagonist, Merck KGaA) Genentech) SR-31747 (IL-1 antagonist,Gemtuzumab (CD33 Sanofi-Synthelabo) antibody, Wyeth Ayerst) CCI-779(mTOR kinase PG2 (Hematopoesis inhibitor, Wyeth) enhancer,Pharmagenesis) Exisulind (PDE-V inhibitor, Immunol ™ (Triclosan oralCell Pathways) irrigation, Endo) CP-461 (PDE-V inhibitor, CellTriacetyluridine (Uridine Pathways) prodrug, Wellstat) AG-2037 (GARTinhibitor, SN-4071 (sarcoma agent, Pfizer) Signature BioScience) WX-UK1(Plasminogen TransMID-107 ™ activator inhibitor, Wilex) (Immunotoxine,KS PBI-1402 (PMN stimulans, Biomedix) ProMetic LifeSciences) PCK-3145(Apoptosis Bortezomib (Proteasome enhancer, Procyon) inhibitor,Millennium) Doranidazole (Apoptosis SRL-172 (T-cell stimulans, enhancer,Pola) SR Pharma) CHS-828 (cytotoxic agent, TLK-286 (Glutathione-S- Leo)transferase inhibitor, Telik) trans-Retinoic acid PT-100 (Growth factor(Differentiator, NIH) agonist, Point Therapeutics) MX6 (Apoptosisenhancer, Midostaurin (PKC inhibitor, MAXIA) Novartis) Apomin (Apoptosisenhancer, Bryostatin-1 (PKC stimulans, ILEX Oncology) GPC Biotech)Urocidine (Apoptosis CDA-II (Apoptosis enhancer, enhancer, Bioniche)Everlife) Ro-31-7453 (Apoptosis SDX-101 (Apoptosis enhancer, La Roche)enhancer, Salmedix) Brostallicin (Apoptosis Ceflatonin (Apoptosisenhancer, Pharmacia) enhancer, ChemGenex)

In a preferred embodiment, a compound of the invention is administeredin combination with one or more known anti-tumor agents, such as thefollowing: estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxics, antiproliferative agents,prenyl proteintransferase inhibitors, HMG-CoA-reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors, angiogenesisinhibitors. The compounds of the present inventions are particularlysuitable for administration at the same time as radiotherapy.

The compounds of the invention are in particular well suited foradministration in combination with radiotherapy. The synergistic effectsof VEGF inhibition in combination with radiotherapy are known to theskilled artisan (WO 00/61186).

The term “estrogen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof estrogen to estrogen receptor—independently from the mode of action.Non-limiting examples of estrogen receptor modulators are tamoxifen,raloxifen, idoxifen, LY353381, LY 117081, toremifen, fulvestrant,4-[7-(2,2-Dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethyl-propanoate,4,4′-Dihydroxybenzophenon-2,4-dinitrophenylhydrazone and SH646.

The term “androgen receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof androgens to androgen receptor—independently from the mode of action.Non-limiting examples of androgen receptor modulators are finasterideand other 5alpha-reductase inhibitors, nilutamide, flutamide,bicalutamide, liarozole and abirateron acetate.

The term “retinoid receptor modulators” in the course of the presentinvention refers to compounds that interfere with or inhibit the bindingof retinoids to retinoid receptor—independently from the mode of action.Non-limiting examples of retinoid receptor modulators are bexaroten,tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,alpha-difluoromethylornithine, ILX23-7553,trans-N-(4′-Hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

The term “cytotoxics” in the course of the present invention refers tocompounds that primarily trigger cell death through direct action oncell function(s) or which interfere with or inhibit cell myosis, such asalkylating agents, tumor necrosis factors, intercalating agents,microtubule inhibitors and topoisomerase inhibitors. Non-limitingexamples of cytotoxics are tirapazimin, sertenef, cachectine,ifosfamide, tasonermine, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcit, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustin,improsulfan-tosylate, trofosfamide, nimustine, dibrospidium-chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-amindichloro(2-methylpyridine)platin, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)-bis-mu-(hexane-1,6-diamine)-muidiamine-platin(II)]bis-[diamine(chloro)platin(II)Hetrachloride,diarizidinylspermine, arsenium trioxide,1-(11-Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantren, mitoxantron, pirarubicin, pinafide,valrubicine, amrubicine, antineoplaston,3′-desamino-3′-morpholino-13-desoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (WO00/50032).

Non-limiting examples of microtubule inhibitors are paclitaxel,vindesine-sulfate, 3′,4′-dideshydro-4′-desoxy-8′-norvincaleukoblastine,docetaxol, rhizoxine, dolastatine, mivobuline-isethionate, auristatine,cemadotine, RPR109881, BMS184476, vinflunine, cryptophycine,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)-benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Non-limiting examples of topoisomerase inhibitors are topotecane,hycaptamine, irinotecane, rubitecane,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusine,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo-[de]-pyrano-[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione,lurtotecane, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecine, BNP1350,BNPI1100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-desoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylendioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-aminoethyl)amino]-benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]-acridine-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxane-then-4-ylmethyl]formamide,N-(2-(dimethyl-amino)-ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)-ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

Non-limiting examples of antiproliferative agents are antisense RNA- andantisense-DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231and INX3001, as well as antimetabolites scuh as enocitabine, carmofur,tegafur, pentostatine, doxifluridine, trimetrexate, fludarabine,capecitabine, galocitabine, cytarabin-ocfosfate, fosteabinesodiumhydrate, raltitrexed, paltitrexide, emitefur, tiazof urine,decitabine, nolatrexed, pemetrexed, nelzarabine,2′-desoxy-2′-methylidencytidine, 2′-fluoromethylen-2′-desoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]N′-(3,4-dichlorophenyl)urea,N6-[4-desoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidine, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazine-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutaminicacid, aminopterine, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diaza-tetracyclo-(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexole, dexrazoxane, methioninase,2′-cyan-2′-desoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and3-aminopyridine-2-carboxaldehyde-thiosemicarbazone.

“Antiproliferative agents” also comprises monoclonal antibodies againstgrowth factors that have not been listed under “angiogenesisinhibitors”, such as trastuzumab, as well as tumor suppressor genes,such as p53.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein in such medicamentcomprises at least one additional pharmacologically active substance(drug, ingredient).

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein the medicament is appliedbefore and/or during and/or after treatment with at least one additionalpharmacologically active substance.

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof the invention is provided.

In a preferred embodiment, the pharmaceutical composition contains atleast one additional compound selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and/or additional pharmaceutically active substance other thanthe compounds of the invention.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises at least one compound of the invention, atleast one pharmacologically active substance other than the compounds ofthe invention as described herein; and a pharmaceutically acceptablecarrier.

A further embodiment of the present invention is a process for themanufacture of said pharmaceutical compositions, characterized in thatone or more compounds according to the invention and one or morecompounds selected from the group consisting of solid, liquid orsemiliquid excipients, auxiliaries, adjuvants, diluents, carriers andpharmaceutically active agents other than the compounds according to theinvention, are converted in a suitable dosage form.

In another aspect of the invention, a kit is provided comprising atherapeutically effective amount of at least one compound of theinvention and/or at least one pharmaceutical composition as describedherein and a therapeutically effective amount of at least one furtherpharmacologically active substance other than the compounds of theinvention.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by oral, parenteral, topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal,transdermal, or buccal routes. Alternatively, or concurrently,administration may be by the oral route. The dosage administered will bedependent upon the age, health, and weight of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. Parenteral administration is preferred. Oraladministration is especially preferred.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art, for exampleas described below:

tablets: mixing of active ingredient/s and auxiliaries, compression ofsaid mixture into tablets (direct compression), optionally granulationof part of mixture before compression.

capsules: mixing of active ingredient/s and auxiliaries to obtain aflowable powder, optionally granulating powder, fillingpowders/granulate into opened capsules, capping of capsules.

semi-solids (ointments, gels, creams): dissolving/dispersing activeingredient/s in an aqueous or fatty carrier; subsequent mixing ofaqueous/fatty phase with complementary fatty/ aqueous phase,homogenization (creams only).

suppositories (rectal and vaginal): dissolving/dispersing activeingredient/s in carrier material liquified by heat (rectal: carriermaterial normally a wax; vaginal: carrier normally a heated solution ofa gelling agent), casting said mixture into suppository forms, annealingand withdrawal suppositories from the forms.

aerosols: dispersing/dissolving active agent/s in a propellant, bottlingsaid mixture into an atomizer.

In general, non-chemical routes for the production of pharmaceuticalcompositions and/or pharmaceutical preparations comprise processingsteps on suitable mechanical means known in the art that transfer one ormore compounds of the invention into a dosage form suitable foradministration to a patient in need of such a treatment. Usually, thetransfer of one or more compounds of the invention into such a dosageform comprises the addition of one or more compounds, selected from thegroup consisting of carriers, excipients, auxiliaries and pharmaceuticalactive ingredients other than the compounds of the invention. Suitableprocessing steps include, but are not limited to combining, milling,mixing, granulating, dissolving, dispersing, homogenizing, castingand/or compressing the respective active and non-active ingredients.Mechanical means for performing said processing steps are known in theart, for example from Ullmann's Encyclopedia of Industrial Chemistry,5th Edition. In this respect, active ingredients are preferably at leastone compound of the invention and one or more additional compounds otherthan the compounds of the invention, which show valuable pharmaceuticalproperties, preferably those pharmaceutical active agents other than thecompounds of the invention, which are disclosed herein.

Particularly suitable for oral use are tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical use are ointments,creams or powders. The compounds of the invention may also belyophilised and the resultant lyophilisates used, for example, for thepreparation of injection preparations. The preparations indicated may besterilised and/or comprise assistants, such as lubricants,preservatives, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, dyes, flavours and/ora plurality of further active ingredients, for example one or morevitamins.

Suitable excipients are organic or inorganic substances, which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the compounds of the invention, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheatstarch, rice starch, potato starch), cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, magnesium stearate, talc, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,polyvinyl pyrrolidone and/or vaseline.

If desired, disintegrating agents may be added such as theabove-mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries include, without limitation,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings, which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharide solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices or to provide a dosage formaffording the advantage of prolonged action, the tablet, dragee or pillcan comprise an inner dosage and an outer dosage component me latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer, which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, acetyl alcohol, solutions of suitable cellulose preparationssuch as acetyl-cellulose phthalate, cellulose acetate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,gelatin, carbohydrates such as lactose or starch, magnesium stearate,talc and petroleum jelly. In particular, tablets, coated tablets,capsules, syrups, suspensions, drops or suppositories are used forenteral administration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The compounds of the invention can also be lyophilized andthe lyophilizates obtained can be used, for example, for the productionof injection preparations.

The preparations indicated can be sterilized and/or can containexcipients such as lubricants, preservatives, stabilizers and/or wettingagents, emulsifiers, salts for affecting the osmotic pressure, buffersubstances, colorants, flavourings and/or aromatizers. They can, ifdesired, also contain one or more further active compounds, e.g. one ormore vitamins.

Other pharmaceutical preparations, which can be used orally includepush-fit capsules made of gelatine, as well as soft, sealed capsulesmade of gelatine and a plasticizer such as glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules, which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatine.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances, which increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran, optionally, thesuspension may also contain stabilizers.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

Possible pharmaceutical preparations, which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatine rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For use in medicine, the compounds of the present invention will be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic bases, e.g. quaternaryammonium salts.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine. As used herein, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. The termalso includes within its scope amounts effective to enhance normalphysiological function. Said therapeutic effective amount of one or moreof the compounds of the invention is known to the skilled artisan or canbe easily determined by standard methods known in the art.

The compounds of the invention and the additional active substances aregenerally administered analogously to commercial preparations. Usually,suitable doses that are therapeutically effective lie in the rangebetween 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mgand especially between 0.5 mg and 100 mg per dose unit. The daily doseis preferably between about 0.001 mg/kg and 10 mg/kg of body weight.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For the purpose of the present invention, all mammalian species areregarded as being comprised. In a preferred embodiment, such mammals areselected from the group consisting of “primate, human, rodent, equine,bovine, canine, feline, domestic animals, cattle, livestock, pets, cow,sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat,dog, guinea pig, hamster, rat, mouse”. More preferably, such mammals arehumans. Animal models are of interest for experimental investigations,providing a model for treatment of human diseases.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician, which advises or attends the therapeutic treatment.

In the case of many disorders, the susceptibility of a particular cellto treatment with the subject compounds may be determined by in vitrotesting. Typically a culture of the cell is combined with a subjectcompound at varying concentrations for a period of time sufficient toallow the active agents to show a relevant reaction, usually betweenabout one hour and one week. For in vitro testing, cultured cells from abiopsy sample may be used.

Even without further details, it is assumed that a person skilled in theart will be able to utilise the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure, which is absolutely not limiting in any way.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that, if necessary, the solventis removed, water is added if necessary, the pH is adjusted, ifnecessary, to between 2 and 10, depending on the constitution of the endproduct, the mixture is extracted with ethyl acetate or dichloromethane,the phases are separated, the organic phase is washed with saturatedNaHCO₃ solution, if desired with water and saturated NaCl solution, isdried over sodium sulfate, filtered and evaporated, and the product ispurified by chromatography on silica gel, by preparative HPLC and/or bycrystallisation. The purified compounds are, if desired, freeze-dried.

Retention time R_(t) [min] determination was carried out by HPLC:

HPLC/MS Conditions A:

column: Chromolith SpeedROD RP-18e, 50×4.6 mm²

gradient: A:B=96:4 to 0:100

flow rate: 2.4 ml/min

eluent A: water+0.05% formic acid

eluent B: acetonitrile+0.04% formic acid

wavelength: 220 nm

mass spectroscopy: positive mode

HPLC/MS Conditions B:

column: Chromolith PerformanceROD RP-18e, 100×3 mm²

gradient: A:B=99:1 to 0:100

flow rate: 2.0 ml/min

eluent A: water+0.05% formic acid

eluent B: acetonitrile+0.04% formic acid

wavelength: 220 nm

mass spectroscopy: positive mode

Mass spectrometry (MS): ESI (electrospray ionisation) (M+H)⁺

List of Abbreviations and Acronyms:

AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOCtert-butoxycarbonyl CDI 1,1′-carbonyl diimidazole, conc concentrated, dday(s), dec decomposition, DIAD diisopropyl azodicarboxylate, DMACNN-dimethylacetamide, DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidinone, DMFNN-dimethylformamide, DMSO dimethylsulfoxide, DPPA diphenylphosphorylazide, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EtOAc ethylacetate, EtOH ethanol (100%), Et₂O diethyl ether, Et₃N triethylamine, hhour(s), MeOH methanol, pet. ether petroleum ether (boiling range 30-60°C.), PPh₃ triphenylphospine, temp. temperature, THF tetrahydrofuran, TFAtrifluoroAcOH, Tf trifluoromethanesulfonyl.

The contents of all cited references are hereby incorporated byreference in their entirety. The invention is explained in more detailby means of the following examples without, however, being restrictedthereto.

EXAMPLES I. Synthesis of Selected Compounds of the Invention

The following compounds were synthesized and characterized. However, itlies in the knowledge of a person skilled in the art to prepare andcharacterize these compounds differently.

I.1 Synthesis of [1,8]Naphthyridine Intermediates Example 1 Synthesis of2,4-dichloro-[1,8]naphthyridine

-   1. A slurry of 4.90 kg (34.5 mol) 2-aminonicotinic acid in 50 l    ethanol was treated with 5.67 l (106 mol) sulfuric acid (98%). The    reaction mixture was stirred for 60 hours at 79° C. The reaction    mixture was then cooled to 40° C. and ethanol was distilled off    under vacuum. The residue was dissolved in a mixture of 45 kg ice    and 55 l water. Then 13 l aqueous sodium hydroxide solution (32% by    weight) was added slowly under stirring and external cooling to    reach a pH of 7. The precipitate was filtered off and washed with    water. The residue was taken up in water, stirred for 1 hour and    filtered. The residue was washed with water and dried under vacuum    yielding 2-amino-nicotinic acid ethyl ester as colourless crystals;    HPLC/MS: 0.99 min, [M+H] 167.

¹H NMR (400 MHz, DMSO) δ=8.22 (dd, J=4.7, 2.0, 1H), 8.07 (dd, J=7.8,1.9, 1H), 7.17 (s, 2H), 6.64 (dd, J=7.8, 4.7, 1H), 4.29 (q, J=7.1, 2H),1.32 (t, J=7.1, 3H).

-   2. 15.2 l (39.7 mol) of a solution of sodium ethylate in ethanol    (20% by weight) was diluted with 50 l ethanol. Then 3.03 l (19.9    mol) diethylmalonate was added and the resulting solution was    stirred for 1 hour at room temperature. Then 3.30 kg (19.9 mol)    2-amino-nicotinic acid ethyl ester was added. The mixture was heated    to 85° C. and the resulting solution was stirred at this temperature    for 65 hours. The reaction mixture was cooled to room temperature    and stirred for 16 hours. The resulting precipitate was filtered off    and dried under vacuum yielding    2,4-dihydroxy-[1,8]naphthyridine-3-carboxylic acid ethyl ester    disodium salt as light brown crystals; HPLC/MS: 1.63 min, [M+H] 235.

¹H NMR (400 MHz, DMSO) δ=8.31 (dd, J=4.6, 1.8, 1H), 8.16 (dd, J=7.6,1.8, 1H), 6.97 (dd, J=7.5, 4.8, 1H), 4.09 (q, J=7.1, 2H), 1.21 (t,J=7.1, 3H).

-   3. A slurry of 2.23 kg (8.01 mol)    2,4-dihydroxy-[1,8]naphthyridine-3-carboxylic acid ethyl ester    disodium salt in 17 l aqueous hydrochloric acid (27% by weight) was    stirred for 16 hours at 72°. Then the reaction mixture was heated to    reflux for 1.5 hours, diluted with 60 l water and cooled to 8° C. At    this temperature 14.9 kg aqueous sodium hydroxide solution (32% by    weight) was added slowly to reach a pH of 5.0 and the resulting    slurry stirred for 16 hours at 5° C. The precipitate was filtered    off, washed with water and dried under vacuum yielding    [1,8]naphthyridine-2,4-diol as colourless crystals; HPLC/MS: 1.12    min, [M+H] 153.

¹H NMR (400 MHz, DMSO) δ=11.61 (bs, 2H), 8.52 (dd, J=4.7, 1.8, 1H), 8.15(dd, J=7.8, 1.8, 1H), 7.22 (dd, J=7.9, 4.7, 1H), 5.79 (s, 1H).

-   4. A slurry of 3.24 g (20.0 mmol) [1,8]naphthyridine-2,4-diol in 28    ml toluene was treated with 5.51 ml (60.0 mmol) phosphorus    oxychloride and stirred at 100° C. for 4 hours. The resulting    two-phase solution was cooled to room temperature and ice was added.    Then 15 ml aqueous sodium hydroxide (50% by weight) was added slowly    to reach a basic pH, while the temperature was kept below 20° C. by    adding more ice. The mixture was extracted with dichloromethane. The    organic phase was dried over sodium sulphate, evaporated and dried    under vacuum to yield 2,4-dichloro-[1,8]naphthyridine as slightly    yellow crystals; HPLC/MS: 1.82 min, [M+H] 199.

¹H NMR (400 MHz, CDCl₃) δ=9.18 (dd, J=4.3, 1.9, 1H), 8.59 (dd, J=8.4,1.9, 1H), 7.63 (m, 2H).

Example 2 Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine

A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1,8]naphthyridine, 8.72 g(50.0 mmol) 5-chloro-2-fluorophenylboronic acid and 5.04 g (60.0 mmol)sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80° C.under nitrogen. 701 mg (1.0 mmol)bis-(triphenylphosphine)-palladium(II)-chloride were added and themixture was stirred for 16 hrs at 80° C. Water was added to the reactionmixture and the precipitate was filtered off, dried in vacuum andrecrystallized from 2-propanol:4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as slightlyyellow crystals; HPLC-MS: 2.49 min, [M+H] 293.

¹H NMR (400 MHz, CDCl₃) δ [ppm]=9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd,J=8.3, 1.9, 1H), 8.37 (dd, J=6.8, 2.7, 1H), 8.10 (d, J=1.6, 1H), 7.56(dd, J=8.4, 4.2, 1H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9,8.8, 1H).

The following compounds were synthesized in an analogous manner:

4-Chloro-2-(2-fluoro-phenyl)-[1,8]naphthyridine, HPLC-MS: 2.30 min,[M+H] 259

4-Chloro-2-(4-fluoro-phenyl)-[1,8]naphthyridine; HPLC-MS: 2.29 min,[M+H] 259

4-Chloro-2-(3-chloro-phenyl)-[1,8]naphthyridine; HPLC-MS: 2.44 min,[M+H] 275

4-Chloro-2-(3-trifluoromethyl-phenyl)-[1,8]naphthyridine; HPLC-MS: 2.49min, [M+H] 309

4-Chloro-2-(2-fluor-5-trifluoromethyl-phenyl)-[1,8]naphthyridine;HPLC-MS: 2.52 min, [M+H] 327

4-Chloro-2-(2,4,5-trifluoro-phenyl)-[1,8]naphthyridine; HPLC-MS: 2.45min, [M+H] 295

4-Chloro-2-(2,5-difluoro-phenyl)-[1,8]naphthyridine; HPLC-MS: 2.31 min,[M+H] 277

Example 3 Synthesis of4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine

A solution of 1.69 g (8.47 mmol) 2,4-dichloro-[1,8]naphthyridine and3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 mltoluene was heated to 80° C. under nitrogen. Then 178 mg (0.254 mmol)bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixturewas stirred for 16 hrs at 80° C. and then cooled to 0° C. in an icebath. The precipitate was filtered off, washed with ice-cold toluene andpetrolether and dried in vacuum. This yields4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felt-likeneedles; HPLC-MS: 2.25 min, [M+H] 256.

¹H-NMR (CDCl₃): δ [ppm]=2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1H), 7.61 (dd,J₁=8.3 Hz, J₂=4.1 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 8.66 (dd, J₁=8.1 Hz,J₂=2.0 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1H), 9.2 (dd, J₁=4.1 Hz,J₂=1.9 Hz, 1H).

Example 4 Synthesis of2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-boronic acid

A slurry of 2.93 g (10.0 mmol)4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 3.30 g (13.0mmol) bis-pinacolato-diboron and 2.94 g (30.0 mmol) potassium acetate in40 ml THF was heated to 80° C. under nitrogen. Then 140 mg (0.20 mmol)bis-(triphenylphosphine)-palladium(II)-chloride were added and thereaction mixture was stirred for 16 hours at 80° C. The mixture wascooled to room temperature and saturated sodium chloride solution wasadded. The mixture was stirred some minutes at room temperature. Theprecipitate thus formed was filtered with suction, washed with water andTHF and dried in vacuo. It was obtained2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid as greysolid; HPLC-MS: [M+H] 303.

¹H NMR (400 MHz, DMSO) δ=9.12 (dd, J=4.1, 1.9, 1H), 8.95 (s, 2H), 8.85(dd, J=8.3, 1.8, 1H), 8.20 (d, J=2.3, 1H), 8.11 (dd, J=6.6, 2.7, 1H),7.67 (m, 2H), 7.51 (dd, J=10.6, 8.9, 1H).

The following compounds were synthesized in an analogous manner:

2-(6-Methylpyridin-2-yl)-[1,8]naphthyridine-4-boronic acid; HPLC-MS:1.07 min, [M+H] 266

2-(2-Fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridine-4-boronic acid;HPLC-MS: [M+H] 337

2-(2,5-Difluoro-phenyl)-[1,8]naphthyridine-4-boronic acid; HPLC-MS; 1.42min, [M+H] 287

2-(2-Fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid; HPLC-MS: [M+H]269

I.2 Synthesis of Final Compounds Example 5 Synthesis of Compound 1

A slurry of 363 mg (1.20 mmol)2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 384 mg(1.00 mmol) 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-c]pyridine(synthesis described in WO2006/052568) and 111 mg (1.32 mmol) sodiumbicarbonate in 2 ml DMF and 1 ml water was heated to 80° C. undernitrogen. Then 41 mg (0.05 mmol)bis-(triphenylphosphine)-palladium(II)-chloride were added. The reactionmixture was stirred for 2 days at 90° C. Water was then added to thereaction mixture and the resulting precipitate was filtered off. Theresidue was purified by preparative HPLC yielding2-(5-chloro-2-fluoro-phenyl)-4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-[1,8]naphthyridineformate as colourless solid; HPLC-MS: 1.57 min, [M+H] 375.

¹H NMR (500 MHz, DMSO) δ=12.39 (s, 1H), 9.20 (dd, J=4.1, 1.9, 1H), 8.94(s, 1H), 8.63 (dd, J=8.4, 1.9, 1H), 8.25 (d, J=5.5, 1H), 8.22 (m, 3H),8.14 (d, J=2.2, 1H), 7.69 (m, 2H), 7.60 (d, J=5.5, 1H), 7.53 (dd,J=10.8, 8.9, 1H).

The following compound was synthesized analogously:

Compound 3; HPLC-MS: 1.58 min, [M+H] 409.

Compound 93

Compound 94

Compound 95

Compound 96

Compound 97

Compound 101

Compound 105

Compound 108

Compound 120

Example 6 Synthesis of Compound 2

A slurry of 151 mg (0.50 mmol)2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 84.9 mg(0.40 mmol) 5-bromoisoquinoline and 44.4 mg (0.53 mmol) sodiumbicarbonate in 2 ml DMF and 1 ml water was heated to 80° C. undernitrogen. Then 16.3 mg (0.02 mmol)bis-(triphenylphosphine)-palladium(II)-chloride were added. The reactionmixture was stirred for 18 hours at 80° C. Water was then added to thereaction mixture and the resulting precipitate was filtered off. Theresidue was chromatographed on a silica gel column withdichloromethane/methanol as eluent yielding2-(5-chloro-2-fluoro-phenyl)-4-isoquinolin-5-yl-[1,8]naphthyridine ascolourless crystals: HPLC/MS: 2.10 min, [M+H] 386.

¹H NMR (500 MHz, DMSO) δ=9.50 (s, 1H), 9.19 (dd, J=4.0, 1.8, 1H), 8.42(d, J=5.9, 1H), 8.38 (d, J=8.0, 1H), 8.23 (dd, J=6.6, 2.7, 1H), 8.07 (d,J=1.7, 1H), 7.95 (dd, J=6.9, 1.0, 1H), 7.91 (m, 1H), 7.82 (dd, J=8.3,1.7, 1H), 7.68 (m, 1H), 7.57 (dd, J=8.3, 4.1, 1H), 7.49 (dd, J=10.7,8.9, 1H), 7.26 (d, J=6.0, 1H).

Compound 19 was synthesized analogously; HPLC-MS: 1.87 min, [M+H] 352.

Using 1-chloro-[2,6]naphthyridine, the following compounds weresynthesized analogously:

Compound 7; HPLC-MS: 1.54 min, [M+H] 350

Compound 23; HPLC-MS: 1.93 min, [M+H] 353

Compound 35; HPLC-MS: 2.03 min, [M+H] 387

Using 3-bromo-furo[2,3-c]pyridine (synthesis described in S. Shiotani etal. J. Heterocycl. Chem. 21, 725 [1984]), Compound 12 was synthesizedanalogously; HPLC-MS 1.86 min, [M+H] 376

Using 5-bromo-8-nitro-isoquinoline, Compound 16 was synthesizedanalogously; HPLC-MS 2.15 min, [M+H] 397

Using 5-bromo-isoquinolin-8-ylamine, Compound 22 was synthesizedanalogously; HPLC-MS 1.54 min, [M+H] 401

The following compounds were/can be synthesized analogously

Compound 37; HPLC/MS: 2.01 min, [M+H] 387

Compound 38; HPLC/MS: 1.50 min, [M+H] 385

Compound 41; HPLC/MS: 1.33 min, [M+H] 367

Compound 42

Compound 43

Compound 50; HPLC/MS: 2.30 min, [M+H]=431

Compound 89

Compound 107

Compound 119

Example 7 Synthesis of Compound 5

-   1. To a solution of 2.44 g (10.0 mmol)    3-iodo-1H-pyrrolo[2,3-c]pyridine and 2.53 g (11.0 mmol)    toluene-4-sulfonic acid 2-methoxy-ethyl ester in 20 ml acetonitrile    3.58 g (11.0 mmol) cesium carbonate were added. The resulting slurry    was stirred for 50 hours at room temperature. The reaction mixture    was filtered with suction and the residue was washed well with    acetonitrile. The filtrate was evaporated and chromatographed on a    silica gel column with dichloromethane/methanol as eluent giving two    isomers separately:

3-Iodo-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-c]pyridine as light brown oil,HPLC/MS: 1.22 min, [M+H] 303

¹H NMR (500 MHz, DMSO) δ=8.88 (s, 1H), 8.23 (d, J=5.5, 1 H), 7.79 (s,1H), 7.25 (dd, J=5.5, 0.8, 1H), 4.49 (t, J=5.1, 2H), 3.69 (t, J=5.1,2H), 3.23 (s, 3H).

3-Iodo-6-(2-methoxy-ethyl)-6H-pyrrolo[2,3-c]pyridine as colourlesscrystals, HPLC/MS: 1.23 min, [M+H] 303

¹H NMR (500 MHz, DMSO) δ=8.71 (s, 1H), 7.99 (s, 1H), 7.79 (dd, J=6.7,1.1, 1H), 7.32 (d, J=6.7, 1H), 4.55 (t, J=5.0, 2H), 3.75 (t, J=5.0, 2H),3.23 (s, 3H).

-   2. A slurry of 181 mg (0.6 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 151    mg (0.5 mmol) 3-iodo-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-c]pyridine    and 55.4 mg (0.66 mmol) sodium bicarbonate in 2 ml DMF and 1 ml    water was heated to 80° C. under nitrogen. Then 20.4 mg (0.025 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 50 hours at 80° C. The reaction    mixture was cooled to room temperature and partitioned between THF    and brine. The organic phase was dried over sodium sulphate and    evaporated. The residue was purified by preparative HPLC yielding    2-(5-chloro-2-fluoro-phenyl)-4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-[1,8]naphthyridine    formate as colourless amorphous solid; HPLC/MS: 1.63 min, [M+H] 433.

Example 8 Synthesis of Compound 4

-   1. A slurry of 6.24 g (30.0 mmol) 5-bromoisoquinoline and 17.5 g (30    mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml    2-propanol was stirred for 50 hours at room temperature. The volume    of the reaction mixture was reduced in vacuo. Brine, saturated    sodium bicarbonate solution and dichloromethane were added. The    organic phase was separated and washed several times with brine. The    organic phase was dried over sodium sulphate and evaporated. The    residue was triturated with tert-butyl-methyl-ether yielding    5-bromo-isoquinoline 2-oxide as colourless crystals, HPLC/MS: 1.51    min, [M+H] 224/226.-   2. A slurry of 605 mg (2.0 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 448    mg (2.0 mmol) 5-bromo-isoquinoline 2-oxide and 202 mg (2.4 mmol)    sodium bicarbonate in 6 ml DMF and 2 ml water was heated to 80° C.    under nitrogen. Then 28 mg (0.04 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 16 hours at 80° C. Water was added    and the resulting precipitate was filtered off, washed with water    and dried under vacuum yielding    2-(5-chloro-2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    as grey solid; HPLC/MS: 2.01 min, [M+H] 402.-   3. A slurry of 473 mg (1.18 mmol)    2-(5-chloro-2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    in 1.2 ml pyridine was cooled to 0° C. 113 μl (1.48 mmol)    methanesulfonyl chloride was added and the resulting solution was    stirred for 16 hours at room temperature. Then 1.5 ml (25 mmol)    ethanolamine were added and the resulting slurry was stirred for 4    hours at room temperature. Water was added, the resulting    precipitate was filtered off and washed with water. The residue was    chromatographed on a silica gel column with dichloromethane/methanol    as eluent yielding    5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-1-ylamine    as yellow crystals; HPLC/MS: 1.65 min, [M+H] 401.

¹H NMR (500 MHz, DMSO) δ=9.17 (dd, J=4.1, 1.9, 1H), 8.42 (d, J=8.4, 1H),8.22 (dd, J=6.6, 2.8, 1H), 8.00 (d, J=2.1, 1H), 7.82 (dd, J=8.4, 1.9,1H), 7.73 (d, J=6.5, 1H), 7.67 (m, 3H), 7.57 (dd, J=8.4, 4.1, 1H), 7.49(dd, J=10.7, 8.9, 1H), 7.00 (s, 2H), 6.25 (d, J=6.0, 1H).

The following compounds were synthesized analogously:

Compound 6; HPLC-MS: 1.26 min, [M+H] 364.

Compound 8; HPLC-MS: 1.75 min, [M+H] 435

Compound 9; HPLC-MS: 1.51 min, [M+H] 367

Example 9 Synthesis of Compound 13

-   1. A slurry of 362 mg (1.2 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 256    mg (2.0 mmol) 3-bromo-furo[2,3-c]pyridine-6-oxide (synthesis    described in S. Yamaguchi et al, J. Heterocycl. Chem. 35, 1249    [1998]) and 181 mg (1.8 mmol) sodium bicarbonate in 6 ml DMF and 1    ml water was heated to 80° C. under nitrogen. Then 28 mg (0.036    mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added.    The reaction mixture was stirred for 40 hours at 80° C. Water was    added and the resulting precipitate was filtered off and washed with    water. The residue was chromatographed on a silica gel column with    dichloromethane/methanol yielding    2-(5-chloro-2-fluoro-phenyl)-4-(6-oxy-furo[2,3-c]pyridin-3-yl)-[1,8]naphthyridine    as light brown solid; HPLC/MS: 1.73 min, [M+H] 392.-   2. A slurry of 743 mg (0.19 mmol)    2-(5-chloro-2-fluoro-phenyl)-4-(6-oxy-furo[2,3-c]pyridin-3-yl)-[1,8]naphthyridine    in 0.4 ml pyridine was cooled to 0° C. 29 μl (0.38 mmol)    methanesulfonyl chloride were added and the resulting solution was    stirred for 40 hours at room temperature. Then 0.3 ml ethanolamine    were added and the resulting slurry was stirred for 18 hours at room    temperature. Water was added; the resulting precipitate was filtered    off and washed with water. The residue was chromatographed on a    silica gel column with dichloromethane/methanol as eluent yielding    3-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-furo[2,3-c]pyridin-7-ylamine    as yellow solid; HPLC/MS: 1.39 min, [M+H] 391.

¹H NMR (400 MHz, DMSO) δ=9.17 (dd, J=4.1, 1.9, 1H), 8.58 (s, 1H), 8.31(dd, J=8.3, 1.9, 1H), 8.19 (m, 2H), 8.03 (d, J=1.9, 1H), 7.67 (m, 2H),7.52 (m, 3H), 7.07 (d, J=5.2, 1H).

Example 10 Synthesis of Compound 14

-   1. A slurry of 1.01 g (6.14 mmol) 1-chloro-[2,6]naphthyridine    (synthesis described in H. J. W. van den Haak et al, J. Heterocycl.    Chem. 18, 1349 [1981]) and 3.57 g (6.14 mmol) magnesium    monoperoxyphthalate hexahydrate (85%) in 25 ml 2-propanol was    stirred for 40 hours at room temperature. The reaction mixture was    diluted with dichloromethane and treated with saturated sodium    bicarbonate solution and brine. The organic phase was separated and    the aqueous phase extracted several times with dichloromethane. The    combined organic phases were washed several times with brine, dried    over sodium sulphate and evaporated. The residue was triturated with    tert-butyl-methyl-ether yielding 1-chloro-[2,6]naphthyridine 6-oxide    as light yellow solid, HPLC/MS: 1.09 min, [M+H] 181.-   2. A slurry of 804 mg (3.0 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 542 mg (3.0    mmol) 1-chloro-[2,6]naphthyridine 6-oxide and 302 mg (3.6 mmol)    sodium bicarbonate in 8 ml DMF and 4 ml water was heated to 80° C.    under nitrogen. Then 42 mg (0.06 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 16 hours at 80° C. The reaction    mixture was cooled to room temperature and partitioned between water    and dichloromethane. The organic phase was dried over sodium    sulphate and evaporated. The residue was chromatographed on a silica    gel column with dichloromethane/methanol as eluent yielding    2-(2-fluoro-phenyl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine    as colourless solid; HPLC/MS: 1.51 min, [M+H] 369.-   3. A slurry of 121 mg (0.33 mmol)    2-(2-fluoro-phenyl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine    in 0.7 ml pyridine was cooled to 0° C. 30 μl (0.39 mmol)    methanesulfonyl chloride was added and the resulting solution was    stirred for 16 hours at room temperature. Then 0.5 ml (8 mmol)    ethanolamine were added and the resulting solution was stirred for    16 hours at room temperature. Water was added, the resulting    precipitate was filtered off, washed with water and dried under    vacuum yielding    5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine    as yellow crystals, HPLC/MS: 1.41 min, [M+H] 368

¹H NMR (400 MHz, DMSO) δ=9.18 (dd, J=4.1, 1.9, 1H), 8.78 (d, J=5.7, 1H),8.30 (d, J=5.7, 1H), 8.21 (td, J=7.9, 1.7, 1H), 8.08 (d, J=2.2, 1H),7.96 (dd, J=8.4, 1.9, 1H), 7.86 (d, J=6.0, 1H), 7.61 (m, 2H), 7.47 (dd,J=11.0, 4.1, 1H), 7.42 (dd, J=11.6, 8.4, 1H), 7.33 (s, 2H), 6.51 (d,J=6.0, 1H).

The following compounds were synthesized analogously:

Compound 11; HPLC-MS: 1.46 min, [M+H] 402

¹H NMR (500 MHz, DMSO) δ=9.19 (dd, J=4.1, 1.8, 1H), 8.77 (d, J=5.7, 1H),8.29 (d, J=5.8, 1H), 8.22 (dd, J=6.6, 2.8, 1H), 8.10 (d, J=1.9, 1H),7.97 (dd, J=8.4, 1.8, 1H), 7.85 (d, J=6.0, 1H), 7.68 (m, 1H), 7.60 (dd,J=8.4, 4.1, 1H), 7.49 (dd, J=10.7, 8.9, 1 H), 7.33 (s, 2H), 6.51 (d,J=6.0, 1H).

Compound 20; HPLC-MS: 1.38 min, [M+H] 386;

Compound 21; HPLC-MS: 1.10 min, [M+H] 365;

Compound 84

Compound 87

Compound 88

Compound 90

Compound 109

Example 11 Synthesis of Compound 15

-   1. A solution of 1.39 g (7.04 mmol) 2-amino-3-bromo-benzonitrile    (synthesis described in J. B. Campbell and T. W. Davenport, Syn.    Commun. 19, 2255 [1989]) in 14 ml 1-butanol was treated with 1.14 g    (14.1 mmol) triazine and 1.2 ml acetic acid and heated to 110° C.    The resulting solution was stirred for 4 days at this temperature.    The reaction mixture was cooled to room temperature and evaporated.    The residue was crystallized from tert.butyl-methyl-ether yielding    8-bromo-quinazolin-4-ylamine as brown solid; HPLC/MS: 1.00 min,    [M+H] 224/226.-   2. A slurry of 332 mg (1.48 mmol) 8-bromo-quinazolin-4-ylamine in 12    ml dichloromethane was treated with 154 μl (1.63 mmol) acetic    anhydride and 132 μl (1.63 mmol) pyridine. The reaction mixture was    stirred for 4 days at room temperature. The reaction mixture was    filtered; the filtrate was evaporated and crystallized from ethanol    yielding N-(8-bromo-quinazolin-4-yl)-acetamide as light brown    crystals; HPLC/MS: 1.37 min, [M+H] 266/288.-   3. A slurry of 156 mg (0.58 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 148 mg (0.56    mmol) N-(8-bromo-quinazolin-4-yl)-acetamide and 58 mg (0.70 mmol)    sodium bicarbonate in 2 ml DMF and 0.5 ml water was heated to 80° C.    under nitrogen. Then 7.8 mg (0.01 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 3 days at 80° C. The reaction    mixture was cooled to room temperature and partitioned between water    and dichloromethane. The organic phase was dried over sodium    sulphate and evaporated. The residue was chromatographed on a silica    gel column with dichloromethane/methanol as eluent yielding    8-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-quinazolin-4-ylamine    as colourless solid; HPLC/MS: 1.41 min, [M+H] 368.

Example 12 Synthesis of Compound 17

A slurry of 50 mg (0.126 mmol)2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine(synthesis see example 6) in 1 ml methanol was treated with 26.5 mg (3.0mmol) potassium methylate. The mixture was stirred at 60° C. undernitrogen for 18 hours. The reaction mixture was cooled to roomtemperature. The solid was filtered off, washed with little methanol anddried under vacuum yielding2-(2-fluoro-phenyl)-4-(8-methoxy-isoquinolin-5-yl)-[1,8]naphthyridine ascolourless solid; HPLC/MS: 1.74 min, [M+H] 382.

¹H NMR (500 MHz, DMSO) δ=9.64 (s, 1H), 9.16 (d, J=2.2, 1H), 8.44 (d,J=5.9, 1H), 8.20 (t, J=7.3, 1H), 8.01 (d, J=1.9, 1H), 7.88 (s, 1H), 7.86(s, 1H), 7.61 (dd, J=13.0, 6.1, 1H), 7.55 (dd, J=8.3, 4.1, 1H), 7.47 (t,J=7.5, 1H), 7.41 (dd, J=11.4, 8.5, 1H), 7.35 (d, J=8.1, 1H), 7.22 (d,J=5.9, 1H), 4.14 (s, 3H).

The following compounds were synthesized analogously:

Compound 99

Example 13 Synthesis of Compound 18

A slurry of 268 mg (1.00 mmol)2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 166 mg (1.00mmol) 4-chloropyrido[3,4-d]pyrimidine, 101 mg (1.20 mmol) sodiumbicarbonate and 4.5 mg (0.020 mmol) palladium(II)acetate in a mixture of4 ml dimethylacetamide and 4 ml ethanol was heated to 80° C. and stirredat this temperature for 18 hours. The reaction mixture was cooled toroom temperature and partitioned between water and dichloromethane. Theorganic phase was dried over sodium sulfate and evaporated. The residuewas chromatographed on a silica gel column with dichloromethane/ethylacetate as eluent yielding4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yq-pyrido[3,4-d]pyrimidine ascolourless crystals; HPLC/MS: 1.91 min, [M+H] 354.

¹H NMR (400 MHz, DMSO) δ=9.73 (s, 1H), 9.66 (d, J=0.9, 1H), 9.22 (dd,J=4.2, 1.9, 1H), 8.75 (d, J=5.8, 1H), 8.23 (m, 3H), 7.71 (dd, J=5.8,1.0, 1H), 7.63 (m, 2H), 7.48 (td, J=7.6, 1.1, 1H), 7.43 (ddd, J=11.6,8.3, 0.9, 1H).

The following compound was synthesized in an anologous manner:

Compound 24; HPLC/MS: 2.09 min, [M+H] 388

Example 14 Synthesis of Compound 36

-   1. A slurry of 65.1 mg (0.24 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 34.6 mg (0.22    mmol) 3-amino-2-chloro-isonicotinonitrile (synthesis described in J.    M Bakke and J Riha, J. Heterocycl. Chem. 38, 99 [2001]) and 22.3 mg    (0.27 mmol) sodium bicarbonate in 0.8 ml DMF and 0.2 ml water was    heated to 80° C. under nitrogen. Then 3 mg (0.04 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 16 hours at 80° C. The reaction    mixture was cooled to room temperature and water was added. The    resulting precipitate was filtered off, washed with water and    chromatographed on a silica gel column with cyclohexane/ethylacetate    as eluent yielding    3-amino-2-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isonicotinonitrile    as light brown solid; HPLC/MS: 1.89 min, [M+H] 342.-   2. A slurry of 11 mg (0.032 mmol)    3-amino-2-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isonicotinonitrile    and 15 mg (0.19 mmol) triazine in 0.1 ml butanol was treated with 10    μl acetic acid and stirred for 7 days at 60° C. The reaction mixture    was evaporated to dryness and purified by preparative HPLC yielding    8-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ylamine    formate; HPLC/MS: 1.47 min, [M+H] 369.

Example 15 Synthesis of Compound 25

A solution of 198 mg (0.50 mmol)2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine(synthesis see example 6) and 131 mg (1.00 mmol)4-(2-hydroxyethyl)morpholine in 1 ml dioxane was treated with 326 mg(1.00 mmol) cesium carbonate (3.0 mmol). The resulting slurry wasstirred at 80° C. for three days. The reaction mixture was cooled toroom temperature and partitioned between water and dichloromethane. Theorganic phase was dried over sodium sulfate and evaporated. The residuewas chromatographed on a silica gel column with dichloromethane/methanolas eluent yielding2-(2-fluoro-phenyl)-4-[8-(2-morpholin-4-yl-ethoxy)-isoquinolin-5-yl]-[1,8]naphthyridineas colourless solid; HPLC/MS: 1.37 min, [M+H] 481.

The following compounds were synthesized in an analogous manner:

Compound 82

Compound 86

Compound 102

Compound 103

Example 16 Synthesis of Compound 26 and Compound 48

-   1. A slurry of 720 mg (2.85 mmol) 5-bromo-8-nitroisoquinoline and    2.48 g (4.27 mmol) magnesium monoperoxyphthalate hexahydrate (85%)    in 11 ml 2-propanol was stirred for 6 days at room temperature. The    reaction mixture was diluted with brine. The solids were filtered    off, washed well with water and dried under vacuum yielding    5-bromo-8-methyl-isoquinoline 2-oxide as yellow solid; HPLC/MS: 1.52    min, [M+H] 269/271.-   2. A slurry of 641 mg (2.39 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 653 mg (2.43    mmol) 5-bromo-8-methyl-isoquinoline 2-oxide and 241 mg (2.897 mmol)    sodium bicarbonate in 5 ml DMF and 2.5 ml water was heated to 80° C.    under nitrogen. Then 34 mg (0.05 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 16 hours at 80° C. The reaction    mixture was cooled to room temperature and partitioned between water    and dichloromethane. The organic phase was dried over sodium sulfate    and evaporated. The residue was chromatographed on a silica gel    column with dichloromethane/methanol as eluent yielding    2-(2-fluoro-phenyl)-4-(8-methyl-2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    as yellow solid; HPLC/MS: 1.87 min, [M+H] 413.-   3. A solution of 206 mg (0.50 mmol)    2-(2-fluoro-phenyl)-4-(8-methyl-2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    in 1 ml methanol was treated with 105 mg (1.5 mmol) potassium    methylate. The mixture was stirred at 60° C. under nitrogen for 18    hours. The reaction mixture was cooled to room temperature and    diluted with water. The resulting precipitate was filtered off,    washed with water and dried unter vacuum yielding    2-(2-fluoro-phenyl)-4-(8-methoxy-2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    as light yellow crystals; HPLC/MS: 1.82 min, [M+H] 398.

¹H NMR (400 MHz, DMSO) δ=9.16 (dd, J=4.1, 1.9, 1H), 8.88 (d, J=1.7, 1H),8.20 (td, J=7.9, 1.8, 1H), 8.04 (dd, J=7.3, 1.9, 1H), 8.00 (d, J=2.3,1H), 7.92 (dd, J=8.3, 1.9, 1H), 7.69 (d, J=8.1, 1H), 7.62 (m, 1H), 7.57(dd, J=8.4, 4.2, 1H), 7.46 (td, J=7.6, 1.1, 1H), 7.41 (ddd, J=11.7, 8.3,0.8, 1H), 7.35 (d, J=8.2, 1H), 7.31 (d, J=7.3, 1H), 4.12 (d, J=16.6,3H).

-   4. A slurry of 125 mg (0.31 mmol)    2-(2-fluoro-phenyl)-4-(8-methoxy-2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    in 0.5 ml pyridine was treated with 29 μl (0.38 mmol)    methanesulfonyl chloride and the resulting orange coloured slurry    was stirred for 16 hours at room temperature. Then 0.4 ml (6 mmol)    ethanolamine were added and the resulting slurry was stirred for 16    hours at room temperature. Water was added, the resulting    precipitate was filtered off and washed with water. The residue was    chromatographed on a silica gel column yielding two isomers:

5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-8-methoxy-isoquinolin-1-ylamineas yellow solid; HPLC/MS: 1.59 min, [M+H] 397

¹H NMR (500 MHz, CDCl₃) δ=9.13 (dd, J=4.2, 2.0, 1H), 8.46 (td, J=7.9,1.8, 1H), 8.04 (d, J=2.4, 1H), 7.84 (dd, J=8.3, 2.0, 1H), 7.73 (d,J=6.0, 1H), 7.50 (d, J=8.1, 1H), 7.45 (tdd, J=7.1, 5.0, 1.9, 1H), 7.35(m, 2H), 7.17 (ddd, J=11.6, 8.2, 0.9, 1H), 6.96 (d, J=8.2, 1H), 6.51 (s,2H), 6.35 (d, J=6.0, 1H), 4.10 (s, 3H).

5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-8-methoxy-isoquinolin-3-ylamineas yellow solid; HPLC/MS: 1.82 min, [M+H] 397

¹H NMR (500 MHz, CDCl₃) δ=9.38 (d, J=0.5, 1H), 9.17 (dd, J=4.1, 2.0,1H), 8.48 (td, J=7.9, 1.9, 1H), 8.08 (d, J=2.5, 1H), 7.95 (dd, J=8.3,2.0, 1H), 7.49 (m, 2H), 7.38 (m, 2H), 7.21 (ddd, J=11.6, 8.2, 0.8, 1H),6.73 (d, J=7.9, 1H), 6.22 (d, J=0.6, 1H), 4.41 (s, 2H), 4.11 (s, 3H).

The following compounds can be or were synthesized in an anologousmanner:

Compound 52

Compound 79

Example 17 Alternative Synthesis of Compound 15

-   1. A slurry of 536 mg (2.00 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 433 mg (2.20    mmol) 2-amino-3-bromo-benzonitrile (synthesis described in J. B.    Campbell and T. W. Davenport, Syn. Commun. 19, 2255 [1989]) and 202    mg (0.27 mmol) sodium bicarbonate in 8 ml DMF and 2 ml water was    heated to 80° C. under nitrogen. Then 28 mg (0.04 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 16 hours at 80° C. The reaction    mixture was cooled to room temperature and water was added. The    resulting precipitate was filtered off, washed with water and    chromatographed on a silica gel column with cyclohexane/ethylacetate    as eluent yielding    2-amino-3-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-benzonitrile    as colourless crystals; HPLC/MS: 2.23 min, [M+H] 341.-   2. A slurry of 193 mg (0.566 mmol)    3-amino-2-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isonicotinonitrile    and 184 mg (2.3 mmol) triazine in 1 ml butanol was treated with 0.1    acetic acid and stirred for 7 days at 60° C. The reaction mixture    was evaporated to dryness and chromatographed on a silica gel column    with dichloromethane/methanol as eluent yielding    8-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-quinazolin-4-ylamine;    HPLC/MS: 1.48 min, [M+H] 368.

¹H NMR (400 MHz, DMSO) δ=9.12 (dd, J=4.1, 1.9, 1H), 8.44 (dd, J=8.3,1.1, 1H), 8.22 (s, 1H), 8.17 (td, J=7.9, 1.7, 1H), 7.92 (m, 4H), 7.80(dd, J=8.3, 1.9, 1H), 7.69 (t, J=7.7, 1H), 7.60 (m, 1H), 7.52 (dd,J=8.3, 4.2, 1H), 7.46 (td, J=7.6, 1.1, 1H), 7.41 (dd, J=11.7, 8.3, 1H).

Example 18 Synthesis of Compound 28 (Reaction Scheme Only)

Compound 29 can be synthesized in an analogous manner.

Example 19 Synthesis of Compound 30 and Compound 31 (Reaction SchemeOnly)

Example 20 Synthesis of Compound 32 and Compound 33 (Reaction SchemeOnly)

Example 21 Synthesis of Compound 34 (Reaction Scheme Only)

Example 22 Synthesis of Compound 39

A slurry of 198 mg (0.50 mmol)2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine(synthesis see example 6) in 1 ml ethane-1,2-diol was treated with 326mg (1.00 mmol) cesium carbonate. The resulting slurry was stirred at 80°C. for two days. The reaction mixture was cooled to room temperature anddiluted with water. The resulting precipitate was filtered off, washedwith water and chromatographed on a silica gel column withdichloromethane/methanol as eluent yielding2-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-8-yloxy}-ethanolas colourless crystals; HPLC/MS: 1.53 min, [M+H] 412.

¹H NMR (400 MHz, DMSO) δ=9.78 (s, 1H), 9.16 (dd, J=3.9, 1.7, 1H), 8.43(d, J=5.9, 1H), 8.21 (td, J=7.8, 1.2, 1H), 8.00 (d, J=2.1, 1H), 7.87(dd, J=8.3, 1.6, 1H), 7.83 (d, J=8.0, 1H), 7.61 (td, J=7.3, 1.4, 1H),7.55 (dd, J=8.3, 4.1, 1H), 7.46 (t, J=7.5, 1H), 7.41 (dd, J=11.5, 8.4,1H), 7.33 (d, J=8.1, 1H), 7.21 (d, J=5.9, 1H), 5.11 (t, J=5.0, 1H), 4.35(t, J=4.6, 2H), 3.95 (m, 2H).

Example 23 Synthesis of Compound 40

A slurry of 184 mg (0.50 mmol)2-(2-fluoro-phenyl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine(synthesis see example 6) in 1 ml methanol was treated with 135 mg (1.25mmol) ethyl chloroformate and stirred for 15 minutes. Then a solution of202 mg (2.00 mmol) triethylamine in 0.5 ml methanol was added and theresulting slurry was stirred at room temperature for 16 hours. Thereaction mixture was treated with 2 N NaOH. The resulting precipitatewas filtered off, washed with water and chromatographed on a silica gelcolumn with ethyl acetate/methanol as eluent yielding2-(2-fluoro-phenyl)-4-(5-methoxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridineas colourless crystals; HPLC/MS: 2.33 min, [M+H] 383.

¹H NMR (500 MHz, DMSO) δ=9.19 (dd, J=4.1, 1.9, 1H), 8.93 (d, J=5.6, 1H),8.21 (m, 2H), 8.13 (d, J=2.2, 1H), 8.10 (d, J=6.1, 1H), 7.99 (dd, J=8.4,1.9, 1H), 7.62 (m, 2H), 7.47 (td, J=7.6, 1.0, 1H), 7.42 (dd, J=11.6,8.3, 1H), 7.08 (d, J=6.1, 1H), 4.15 (s, 3H).

Example 24 Synthesis of Compound 44 and Compound 45 (Reaction SchemeOnly)

The following compound can be synthesized in an anologous manner:

Compound 53

Compound 61

Example 25 Synthesis of Compound 46 and Compound 47 (Reaction SchemeOnly)

The following compound can be synthesized in an anologous manner:

Compound 56

Example 26 Synthesis of Compound 4 and Compound 49

A slurry of 569 mg (1.42 mmol)2-(5-chloro-2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine(synthesis see example 8) in 2.8 ml pyridine was treated with 324 mg(1.70 mmol) p-toluenesulfonyl chloride and the resulting solution wasstirred for 2 hours at room temperature. Then 2.1 ml (35.1 mmol)ethanolamine were added and the mixture was stirred for 2 hours at roomtemperature. Water was added, the resulting precipitate was filtered offand washed with water. The residue was chromatographed on a silica gelcolumn with ethylacetate/methanol as eluent yielding two isomers:

Compound 4 (see example 8)

5-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-3-ylamineas light yellow solid; HPLC/MS: 2.06 min, [M+H] 401

¹H-NMR (400 MHz, CDCl₃) δ=9.10 (dd, J=4.2, 2.0, 1H), 8.91 (s, 1H), 8.42(dd, J=6.7, 2.7, 1H), 7.98 (d, J=2.3, 1H), 7.89 (d, J=8.2, 1H), 7.81(dd, J=8.3, 2.0, 1H), 7.48 (dd, J=7.0, 1.1, 1H), 7.33 (m, 3H), 7.07 (dd,J=10.8, 8.8, 1H), 6.14 (s, 1H), 4.35 (s, 2H).

Example 27 Synthesis of Compound 51 (Reaction Scheme Only)

Example 28 Synthesis of Compound 54 and Compound 55 (Reaction SchemeOnly)

Example 29 Synthesis of Compound 57 (Reaction Scheme Only)

The following compound can be synthesized in an anologous manner:

Compound 58

Example 30 Synthesis of Compound 59 and Compound 60 (Reaction SchemeOnly)

The following compound can be synthesized in an anologous manner:

Compound 58

Example 31 Synthesis of Compound 64 and Compound 65

-   1. A suspension of 573 mg (2.0 mmol) 5,8-dibromoisoquinoline, 458 mg    (2.2 mmol)    1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole,    849 mg (4.0 mmol) tri-potassium-phosphate trihydrate and 140 mg    (0.20 mmol) bis-(triphenylphosphine)-palladium(II)-chloride in 4 ml    1,2-dimethoxyethane were stirred for 18 hours at 80° C. under    nitrogen. The reaction mixture was cooled to room temperature,    diluted with THF and filtered. The filtrate was evaporated and the    residue was chromatographed on a silica gel column with    ethylacetate/methanol as eluent. The two isomers were obtained    separately.

First eluted isomer: 8-bromo-5-(1-methyl-1H-pyrazol-4-yl)-isoquinolineas colourless crystals; HPLC/MS 1.90 min, [M+H]=288/290.

Second eluted isomer: 5-bromo-8-(1-methyl-1H-pyrazol-4-yl)-isoquinolineas yellow crystals; HPLC/MS (A) 2.02 min, [M+H]=288/290.

-   2. A suspension of 135 mg (0.47 mmol)    8-bromo-5-(1-methyl-1H-pyrazol-4-yl)-isoquinoline, 126 mg (0.47    mmol) 2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and 47.4    mg (0.56 mmol) sodium hydrogen carbonate in 1.2 ml DMF and 0.6 ml    water was heated to 80° C. under nitrogen. Then 6.6 mg (0.009 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 18 hours at 80° C. The reaction    mixture was cooled to room temperature and partitioned between water    and dichloromethane. The organic phase was dried over sodium sulfate    and evaporated. The residue was chromatographed on a silica gel    column with ethyl acetate/methanol as eluent yielding    2-(2-fluoro-phenyl)-4-[5-(1-methyl-1H-pyrazol-4-yl)-isoquinolin-8-yl]-[1,8]naphthyridine    as colourless solid; HPLC/MS (A): 1.87 min, [M+H] 432.

¹H NMR (400 MHz, DMSO) δ=9.19 (dd, J=4.1, 1.9, 1H), 8.83 (d, J=0.9, 1H),8.60 (d, J=6.0, 1H), 8.27 (s, 1H), 8.23 (td, J=7.9, 1.8, 1H), 8.17 (dd,J=6.0, 0.9, 1H), 8.11 (d, J=2.4, 1H), 7.95 (d, J=7.4, 1H), 7.91 (m, 2H),7.80 (d, J=7.4, 1H), 7.62 (m, 1H), 7.57 (dd, J=8.4, 4.1, 1H), 7.47 (td,J=7.6, 1.1, 1H), 7.41 (ddd, J=11.6, 8.3, 1.0, 1H), 4.01 (s, 3H).

-   3. Similarly was prepared:    2-(2-Fluoro-phenyl)-4-[8-(1-methyl-1H-pyrazol-4-yl)-isoquinolin-5-yl]-[1,8]naphthyridine    as yellow solid; HPLC/MS (A): 1.84 min, [M+H] 432.

¹H NMR (400 MHz, DMSO) δ=9.66 (d, J=0.9, 1H), 9.18 (dd, J=4.1, 1.9, 1H),8.45 (d, J=5.9, 1H), 8.33 (s, 1H), 8.22 (td, J=7.9, 1.8, 1H), 8.06 (d,J=2.3, 1H), 7.95 (d, J=0.8, 1H), 7.93 (d, J=7.4, 1H), 7.87 (dd, J=8.4,1.9, 1H), 7.83 (d, J=7.4, 1H), 7.62 (dddd, J=8.2, 7.2, 5.1, 1.9, 1H),7.56 (dd, J=8.4, 4.1, 1H), 7.47 (td, J=7.6, 1.1, 1H), 7.41 (ddd, J=11.7,8.3, 1.0, 1H), 7.29 (dd, J=5.9, 0.9, 1H), 4.02 (s, 3H).

Example 32 Synthesis of Compound 68

-   1. A suspension of 2.11 g (7.74 mmol)    4-iodo-2H-[2,7]naphthyridin-1-one (for the preparation see A. Zhang    et al, J. Comb. Chem. 9, page 916, 2007) and 3.08 g (11.6 mmol)    triphenylphosphine in 30 ml THF and 2.4 ml (77 mmol) ethane-1,2-diol    is treated with 2.40 ml (11.6 mmol) diisopropyl azodicarboxylate    under external cooling with ice. The resulting solution was stirred    for 3 days at room temperature. The precipitate that had formed was    filtered off, washed with tert.butyl-methyl-ether and dried under    vacuum: 2-(2-Hydroxy-ethyl)-4-iodo-2H-[2,7]naphthyridin-1-one as    colourless solid; HPLC/MS (A): 1.29 min, [M+H]=317.

¹H NMR (400 MHz, DMSO) δ=9.28 (d, J=0.6, 1H), 8.84 (d, J=5.6, 1H), 8.13(s, 1H), 7.47 (dd, J=5.6, 0.7, 1H), 4.89 (s, 1H), 4.05 (t, J=5.4, 2H),3.67 (t, J=5.4, 2H).

-   2. A slurry of 158 mg (0.5 mmol)    2-(2-Hydroxy-ethyl)-4-iodo-2H-[2,7]naphthyridin-1-one, 166 mg (0.55    mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid    and 50.4 mg (0.6 mmol) sodium bicarbonate in 2 ml DMF and 1 ml water    was heated to 80° C. under nitrogen. Then 7.0 mg (0.01 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added. The    reaction mixture was stirred for 18 hours at 80° C. Water was added    and the resulting precipitate was filtered off and washed with    water. The residue was chromatographed on a silica gel column with    dichloromethane/methanol yielding    4-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-2-(2-hydroxy-ethyl)-2H-[2,7]naphthyridin-1-one    as light brown solid; HPLC/MS

(A): 1.74 min, [M+H] 447.

¹H NMR (400 MHz, DMSO) δ=9.50 (d, J=0.6, 1H), 9.19 (dd, J=4.1, 1.9, 1H),8.62 (d, J=5.6, 1H), 8.27 (dd, J=8.4, 1.9, 1H), 8.20 (dd, J=6.6, 2.8,1H), 8.08 (d, J=2.1, 1H), 7.95 (s, 1H), 7.68 (ddd, J=8.8, 4.2, 2.8, 1H),7.62 (dd, J=8.4, 4.2, 1H), 7.50 (dd, J=10.8, 8.8, 1H), 7.06 (dd, J=5.6,0.6, 1H), 4.94 (t, J=5.7, 1H), 4.13 (m, 2H), 3.77 (dt, J=8.1, 5.8, 2H).

The following compounds were synthesized in an anologous manner:

Compound 67

Compound 72

Compound 74

Compound 75

Compound 81

Example 33 Synthesis of Compound 76 and Compound 77

-   1. A suspension of 544 mg (2.00 mmol)    4-iodo-2H-[2,7]naphthyridin-1-one, 795 mg (3.00 mmol)    triphenylphosphine and 371 μl (3.00 mmol) 2-morpholino-ethanol in 50    ml THF is treated with 620 μl (3.00 mmol) diisopropyl    azodicarboxylate under external cooling with ice. The reaction    mixture was stirred for 18 hours at room temperature. The solids    were filtered off; the filtrate was evaporated and the residue was    chromatographed on a silica gel column with ethyl acetate/methanol    as eluent yielding the two isomer separately.

First eluted isomer:4-Iodo-2-(2-morpholin-4-yl-ethyl)-2H-[2,7]naphthyridin-1-one ascolourless crystals; HPLC/MS (A): 1.05 min, [M+H]=386.

¹H NMR (400 MHz, DMSO) δ=9.28 (s, 1H), 8.83 (d, J=5.6, 1H), 8.20 (s,1H), 7.47 (d, J=5.6, 1H), 4.09 (t, J=6.3, 2H), 3.53 (m, 4H), 2.60 (t,J=6.3, 2H), 2.44 (m, 4H).

Second eluted isomer:4-Iodo-1-(2-morpholin-4-yl-ethoxy)-[2,7]naphthyridine as colourlesscrystals; HPLC/MS (A): 1.34 min, [M+H]=386.

¹H NMR (400 MHz, DMSO) δ=9.41 (s, 1H), 8.88 (d, J=5.8, 1H), 8.61 (s,1H), 7.70 (d, J=5.8, 1H), 4.63 (t, J=5.7, 2H), 3.56 (m, 4H), 2.84 (t,J=5.7, 2H), 2.52 (m, 4H).

-   2. A slurry of 154 mg (0.4 mmol)    4-iodo-1-(2-morpholin-4-yl-ethoxy)-[2,7]naphthyridine, 133 mg (0.44    mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid    and 40.3 mg (0.48 mmol) sodium hydrogen carbonate in 1.6 ml DMF and    0.8 ml water was heated to 80° C. under nitrogen. Then 5.6 mg (0.008    mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and    the reaction mixture was stirred for 18 hours at 80° C. Water was    added and the resulting precipitate was filtered off and washed with    water. The residue was chromatographed on a silica gel column with    ethyl acetate/methanol yielding    2-(5-chloro-2-fluoro-phenyl)-4-[1-(2-morpholin-4-yl-ethoxy)-[2,7]naphthyridin-4-yl]-[1,8]naphthyridine    as light yellow crystals; HPLC/MS (A): 1.67 min, [M+H] 516.

¹H NMR (500 MHz, DMSO) δ=9.65 (s, 1H), 9.21 (d, J=2.2, 1H), 8.68 (d,J=5.7, 1H), 8.40 (s, 1H), 8.23 (dd, J=6.6, 2.8, 1H), 8.10 (d, J=1.8,1H), 8.02 (dd, J=8.4, 1.8, 1H), 7.69 (ddd, J=8.6, 4.0, 3.0, 1H), 7.60(dd, J=8.4, 4.1, 1H), 7.51 (dd, J=10.7, 8.9, 1H), 7.27 (d, J=5.8, 1 H),4.78 (t, J=5.3, 2H), 3.62 (m, 4H), 2.94 (t, J=5.2, 2H), 2.60 (s, 4H).

-   3. A slurry of 154 mg (0.4 mmol)    4-iodo-2-(2-morpholin-4-yl-ethyl)-2H-[2,7]naphthyridin-1-one, 133 mg    (0.44 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and    40.3 mg (0.48 mmol) sodium hydrogen carbonate in 1.6 ml DMF and 0.8    ml water was heated to 80° C. under nitrogen. Then 5.6 mg (0.008    mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and    the reaction mixture was stirred for 18 hours at 80° C. Water was    added and the resulting precipitate was filtered off, washed with    water and dried under vacuum. The solid was recrystallized twice    from isopropanol yielding    4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-2-(2-morpholin-4-yl-ethyl)-2H-[2,7]naphthyridin-1-one    as slightly yellow crystals; HPLC/MS (A): 1.67 min, [M+H] 516.

¹H NMR (400 MHz, DMSO) δ=9.50 (s, 1H), 9.21 (d, J=2.2, 1H), 8.62 (d,J=4.9, 1H), 8.22 (m, 2H), 8.08 (d, J=1.9, 1H), 8.01 (s, 1H), 7.68 (ddd,J=8.7, 4.0, 3.0, 1H), 7.63 (dd, J=8.3, 4.1, 1H), 7.51 (dd, J=10.8, 8.9,1H), 7.04 (d, J=5.5, 1H), 4.16 (m, 2H), 3.51 (s, 4H), 2.69 (m, 2H), 2.46(d, J=4.2, 4H).

The following compounds were synthesized in an anologous manner:

Compound 78

Compound 91

Compound 98

Compound 100

Compound 104

Example 34 Synthesis of Compound 69

A solution of 37 mg (0.10 mmol)5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylaminein 0.5 ml acetic acid was treated with 20.4 mg (0.20 mmol) acetic acidanhydride and heated to 80° C. The reaction mixture was stirred at thistemperature for 18 hours. The reaction mixture was cooled to roomtemperature and partitioned between 25% aqueous ammonia anddichloromethane. The organic phase was dried over sodium sulphate andevaporated. The residue was triturated with tert-butyl-methyletheryieldingN-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamideas brown crystals; HPLC/MS (A) 1.64 min, [M+H] 410.

¹H NMR (500 MHz, DMSO) δ=10.81 (s, 1H), 9.20 (dd, J=4.1, 1.9, 1H), 8.91(d, J=5.9, 1H), 8.39 (d, J=5.9, 1H), 8.21 (td, J=7.9, 1.7, 1H), 8.15 (d,J=2.1, 1H), 8.12 (d, J=5.9, 1H), 7.99 (dd, J=8.4, 1.9, 1H), 7.62 (m,2H), 7.47 (td, J=7.7, 1.0, 1H), 7.42 (m, 2H), 2.28 (s, 3H).

Example 35 Synthesis of Compound 71

A suspension of 551 mg (1.5 mmol)5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylaminein 10 ml DMF was treated with 108 mg (4.50 mmol) sodium hydride andstirred for 1 h at room temperature. Then 356 mg (2.25 mmol)dimethylaminoacetyl chloride hydrochloride were added and the reactionmixture was stirred for 18 h at room temperature. The reaction mixturewas partitioned between water and dichloromethane. The organic phase wasdried over sodium sulfate and evaporated. The residue waschromatographed on a silica gel column with ethyl acetate/methanol aseluent yielding2-dimethylamino-N-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamideas brown amorphous solid; HPLC/MS (B) 1.64 min, [M+H] 453.

The following compounds were synthesized in an anologous manner:

Compound 73

Example 36 Synthesis of Compound 110 and Compound 112

-   1. To a solution of 19.0 g (125 mmol) 3-amino-isonicotinic acic    methyl ester in 125 ml ethyl acetate was added portionwise 29.4 g    (262 mmol) potassium-tert.butylate under nitrogen. The reaction    mixture was heated to 75° C. and stirred at this temperature for 18    hours under nitrogen. The reaction mixture was cooled to room    temperature and 400 ml water were added. The organic phase was    separated and the aqueous phase was extracted with ethyl acetate and    tert-butyl-methylether. All organic phases were discarded. The    aqueous phase was acidified with 2 N HCl to a pH of 6. The resulting    precipitate was filtered off, washed with water and dried under    vacuum yielding [1,7]naphthyridine-2,4-diol as colourless crystals;    HPLC/MS (A): 0.86 min, [M+H]=163.

¹H NMR (400 MHz, DMSO) δ=11.29 (b, 2H), 8.60 (d, J=0.5, 1 H), 8.27 (d,J=5.2, 1H), 7.66 (dd, J=5.2, 0.5, 1H), 5.82 (s, 1H).

-   2. A suspension of 2.59 g (16.0 mmol) [1,7]naphthyridine-2,4-diol in    32 ml 1-butyl-1-methyl-pyrrolidinium trifluoromethylsulfonate was    treated with 15.1 g (52.8 mmol) phosphorus oxybromide. The reaction    mixture was stirred for 18 h at 85° C. The reaction mixture was    cooled to room temperature. Ice and 12 ml 50% aqueous NaOH were    added. The resulting precipitate was filtered off, washed with water    and dried under vacuum yielding 2,4-dibromo-[1,7]naphthyridine as    light brown crystals; HPLC/MS (A): 2.18 min, [M+H]=289.

¹H NMR (400 MHz, CDCl₃) δ=9.37 (s, 1H), 8.70 (d, J=5.8, 1H), 7.97 (s,1H), 7.86 (d, J=5.8, 1H).

-   3. A suspension of 924 mg (3.21 mmol) 2,4-dibromo-[1,7]naphthyridine    in 3.2 ml water and 1.9 ml dioxane was treated with 2.89 ml 47%    aqueous hydrobromic acid. The resulting brown solution was stirred    for 18 hours at 80° C. The reaction mixture was cooled to room    temperature and 50% aqueous NaOH was added to adjust the pH to 7.    The resulting precipitate was filtered off, washed with water and    dried under vacuum yielding 4-bromo-1H-[1,7]naphthyridin-2-one as    light brown crystals; HPLC/MS (A): 1.38 min, [M+H]=225/227.

¹H NMR (400 MHz, DMSO) δ=12.28 (s, 1H), 8.68 (s, 1H), 8.44 (d, J=5.4,1H), 7.69 (d, J=5.4, 1H), 7.30 (s, 1H).

-   4. A solution of 116 mg (0.50 mmol)    4-bromo-1H-[1,7]naphthyridin-2-one and 102 mg (0.55 mmol)    N-(2-chloroethyl)-morpholinium chloride in 1.4 ml DMF was treated    with 261 mg (0.80 mmol) cesium carbonate and the reaction mixture    was stirred for 18 hours at room temperature. The reaction mixture    was partitioned between water and dichloromethane. The organic phase    was dried over sodium sulfate and evaporated. The residue was    chromatographed on a silica gel column with dichloromethane/methanol    as eluent yielding the two isomers separately.

First eluted isomer:4-Bromo-2-(2-morpholin-4-yl-ethoxy)-[1,7]naphthyridine as colourlesscrystals; HPLC/MS (A): 1.19 min, [M+H]=338/340.

¹H NMR (400 MHz, DMSO) δ=9.14 (s, 1H), 8.62 (d, J=5.6, 1H), 7.88 (d,J=5.6, 1H), 7.79 (s, 1H), 4.59 (t, J=5.7, 2H), 3.56 (m, 4H), 2.76 (t,J=5.7, 2H), 2.5 (m, 4H).

Second eluted isomer:4-Bromo-1-(2-morpholin-4-yl-ethyl)-1H-[1,7]naphthyridin-2-one ascolourless crystals; HPLC/MS (A): 1.08 min, [M+H]=338/340.

¹H NMR (400 MHz, DMSO) δ=9.02 (s, 1H), 8.53 (d, J=5.3, 1H), 7.79 (d,J=5.3, 1H), 7.43 (s, 1H), 4.45 (t, J=6.8, 2H), 3.51 (m, 4H), 2.60 (t,J=6.8, 2H), 2.5 (m, 4H).

-   5. A slurry of 69.3 mg (0.21 mmol)    4-bromo-1-(2-morpholin-4-yl-ethyl)-1H-[1,7]naphthyridin-2-one, 68.1    mg (0.23 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and    20.6 mg (0.25 mmol) sodium hydrogen carbonate in 1.6 ml DMF and 0.8    ml water was heated to 80° C. under nitrogen. Then 2.8 mg (0.004    mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and    the reaction mixture was stirred for 18 hours at 80° C. Water was    added and the resulting precipitate was filtered off and washed with    water. The residue was triturated with tert-butyl-methylether    yielding    4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-1-(2-morpholin-4-yl-ethyl)-1H-[1,7]naphthyridin-2-one    as light yellow crystals; HPLC/MS (A): 1.59 min, [M+H] 516.-   6. A slurry of 31.4 mg (0.093 mmol)    4-bromo-2-(2-morpholin-4-yl-ethoxy)-[1,7]naphthyridine, 30.9 mg    (0.102 mmol)    2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and    9.4 mg (0.11 mmol) sodium hydrogen carbonate in 0.7 ml DMF and 0.4    ml water was heated to 80° C. under nitrogen. Then 1.3 mg (0.002    mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and    the reaction mixture was stirred for 18 hours at 80° C. Water was    added and the resulting precipitate was filtered off, washed with    water and dried. The residue was chromatographed on a silica gel    column with dichloromethane/methanol as eluent yielding    4-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-2-(2-morpholin-4-yl-ethoxy)-[1,7]naphthyridine    as colourless crystals; HPLC/MS (A) 1.64 min, [M+H] 516.

¹H NMR (500 MHz, DMSO) δ=9.26 (s, 1H), 9.21 (dd, J=3.9, 1.6, 1 H), 8.37(d, J=5.6, 1H), 8.21 (dd, J=6.5, 2.7, 1H), 8.12 (d, J=1.1, 1H), 7.96(dd, J=8.3, 1.5, 1H), 7.68 (m, 1H), 7.60 (dd, J=8.3, 4.1, 1 H), 7.50 (m,2H), 7.20 (d, J=5.6, 1 H), 4.68 (m, 2H), 3.59 (m, 4H), 2.82 (m, 2H),2.53 (m, 4H).

Example 37 Synthesis of Compound 111

-   1. A suspension of 1.99 g (12.3 mmol) [1,7]naphthyridine-2,4-diol in    25 ml toluene was treated with 3.38 ml (36.7 mmol) phosphorus    oxychloride and stirred at 80° C. for 18 hours. The reaction mixture    was cooled to room temperature; water, 7 ml 50% aqueous NaOH and    dichloromethane were added. The mixture was filtered, the organic    phase was separated, dried over sodium sulfate and evaporated    yielding 2,4-dichloro-[1,7]naphthyridine as light brown crystals;    HPLC/MS (B): 2.43 min, [M+H]=199.-   2. Under nitrogen, a solution of 1.19 g (6.00 mmol)    2,4-dichloro-[1,7]naphthyridine, 1.72 ml (18.0 mmol) propyl formate    and 84 mg (0.12 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride in 24 ml DMF was    treated with a solution of 1.21 g (14 mmol) sodium hydrogen    carbonate in 12 ml water and the reaction mixture was stirred at    80° C. for 3 days. The reaction mixture was cooled to room    temperature and partitioned between dichloromethane and aqueous 1 N    NaOH solution. The organic phase was dried over sodium sulphate and    evaporated. The residue was chromatographed on a silica gel column    with cyclohexane/ethyl acetate as eluent yielding    4-chloro-[1,7]naphthyridine as colourless crystals; HPLC/MS (B):    1.84 min, [M+H]=165.-   3. A suspension of 112 mg (0.42 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 65.8 mg (0.40    mmol) 4-chloro-[1,7]naphthyridine and 42 mg (0.50 mmol) sodium    hydrogen carbonate in 1 ml DMF and 0.5 ml water was heated to 80° C.    under nitrogen. Then 5.6 mg (0.008 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added and the    reaction mixture was stirred for 18 hours at 80° C. Water was added    and the resulting precipitate was filtered off, washed with water    and dried. The residue was chromatographed on a silica gel column    with ethyl acetate/methanol as eluent yielding    4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridine as    light yellow crystals; HPLC/MS (B) 2.30 min, [M+H] 353.

¹H NMR (500 MHz, DMSO) δ=9.57 (s, 1H), 9.27 (d, J=4.3, 1H), 9.20 (dd,J=4.1, 1.9, 1H), 8.54 (d, J=5.8, 1H), 8.20 (td, J=7.9, 1.7, 1H), 8.11(d, J=2.1, 1H), 7.98 (d, J=4.3, 1H), 7.91 (dd, J=8.3, 1.8, 1H), 7.62 (m,1H), 7.58 (dd, J=8.4, 4.1, 1H), 7.47 (m, 1H), 7.41 (m, 2H).

Example 38 Synthesis of Compound 113

-   1. A slurry of 266 mg (1.62 mmol) 4-chloro-[1,7]naphthyridine and    943 mg (1.62 mmol) magnesium monoperoxyphthalate hexahydrate (85%)    in 3 ml 2-propanol was stirred for 2 hours at 60° C. The reaction    mixture was cooled to room temperature and treated with saturated    sodium carbonate solution. This mixture was extracted twice with    THF. The organic phase was washed with saturated sodium chloride    solution, dried over sodium sulfate and evaporated. The residue was    chromatographed on a silica gel column with ethyl acetate/methanol    as eluent yielding 4-chloro-[1,7]naphthyridine 7-oxide as slightly    brown solid; HPLC/MS (B): 1.38 min, [M+H]=181

¹H NMR (400 MHz, DMSO) δ=8.98 (d, J=1.7, 1H), 8.91 (d, J=4.8, 1H), 8.36(dd, J=7.3, 1.8, 1H), 8.10 (d, J=7.3, 1H), 7.82 (d, J=4.8, 1H).

-   2. A suspension of 205 mg (0.76 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 131 mg (0.73    mmol) 4-chloro-[1,7]naphthyridine 7-oxide and 76 mg (0.91 mmol)    sodium hydrogen carbonate in 2 ml DMF and 1 ml water was heated to    80° C. under nitrogen. Then 10 mg (0.015 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added and the    reaction mixture was stirred for 18 hours at 80° C. Water was added    and the resulting precipitate was filtered off, washed with water    and dried. The residue was chromatographed on a silica gel column    with ethyl acetate/methanol as eluent yielding    4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridine    7-oxide as grey crystals; HPLC/MS (B) 1.84 min, [M+H] 369.-   3. A suspension of 119 mg (0.32 mmol)    4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridine    7-oxide in 0.66 ml pyridine was treated with 53.9 mg (0.47 mmol)    methanesulfonyl chloride. The mixture was stirred for 2 h at 80° C.    and then stirred at room temperature for 16 hours. Then 115 mg (1.95    mmol) propylamine were added and the reaction mixture was stirred    for 1 hour at room temperature. Water was added to the reaction    mixture; the resulting precipitate was filtered off, washed with    water and dried. The residue was chromatographed on a silica gel    column with dichloromethane/methanol as eluent yielding    4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridin-8-ylamine    as yellow solid; HPLC/MS (B) 1.75 min, [M+H] 368.-   ¹H NMR (400 MHz, DMSO) δ=9.19 (dd, J=4.1, 1.9, 1H), 8.97 (d, J=4.4,    1H), 8.19 (td, J=7.9, 1.8, 1H), 8.04 (d, J=2.2, 1H), 7.89 (dd,    J=8.3, 1.9, 1H), 7.82 (d, J=4.4, 1H), 7.77 (d, J=5.9, 1H), 7.61 (m,    2H), 7.44 (m, 2H), 7.14 (s, 2H), 6.30 (d, J=5.9, 1H).

Example 39 Synthesis of Compound 115

-   1.A slurry of 1.46 g (10.0 mmol) 2,6-naphthyridine-1(2H)-one in 30    ml 1 N aqueous NaOH solution was treated with 5.08 g (20.0 mmol)    iodine and stirred for 40 hours at 80° C. The reaction mixture was    cooled to room temperature and 70 ml water were added. The solid was    filtered off, washed with water and dried under vacuum yielding    4-iodo-2H-[2,6]naphthyridin-1-one as brown ; HPLC/MS (B): 1.72 min,    [M+H]=273.

¹H NMR (400 MHz, DMSO) δ=11.86 (s, 1H), 8.95 (s, 1H), 8.74 (d, J=5.2,1H), 7.95 (dd, J=5.2, 0.8, 1H), 7.70 (d, J=4.4, 1H).

-   2. Nitrogen was bubbled through a suspension of 1.45 g (5.34 mmol)    4-iodo-2H-[2,6]naphthyridin-1-one, 3.48 g (10.7 mmol) cesium    carbonate, 193 mg (1.07 mmol) 1,10-phenanthroline and 102 mg (0.534    mmol) copper(I)iodide in 10 ml methanol and subsequently was reacted    at 120° C. for 7 hours in a microwave. The reaction mixture was    cooled to room temperature and the solids were filtered off. The    filtrate was evaporated and chromatographed on a silica gel column    with ethyl acetate/methanol as eluent yielding    4-methoxy-2H-[2,6]naphthyridin-1-one as colourless crystals; HPLC/MS    (B): 1.36 min, [M+H]=177.-   3. A suspension of 116 mg (0.66 mmol)    4-methoxy-2H-[2,6]naphthyridin-1-one in 1 ml chlorobenzene was    treated with 0.12 ml phosphorus oxychloride and stirred for 18 hours    at 100° C. The reaction mixture was cooled to room temperature and    partitioned between aqueous 2 N NaOH and dichloromethane. The    organic phase was dried over sodium sulfate and evaporated. The    residue was chromatographed on a silica gel column with ethyl    acetate/methanol as eluent yielding    1-chloro-4-methoxy-[2,6]naphthyridine as slightly yellow solid;    HPLC/MS (B) 2.19 min, [M+H] 195.-   4. A suspension of 137 mg (0.51 mmol)    2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 99.3 mg (0.51    mmol) 1-chloro-4-methoxy-[2,6]naphthyridine and 7.2 mg (0.010 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride in 1 ml DMF and 0.5    ml water was heated to 80° C. under nitrogen. Then 51 mg (0.61 mmol)    sodium hydrogen carbonate were added and the reaction mixture was    stirred for 40 hours at 80° C. Water was added and the resulting    precipitate was filtered off, washed with water and dried. The    residue was purified by preparative HPLC yielding    2-(2-fluoro-phenyl)-4-(4-methoxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine    as slightly yellow solid; HPLC/MS (B) 2.49 min, [M+H] 383

¹H NMR (400 MHz, DMSO) δ=9.73 (d, J=0.8, 1H), 9.19 (dd, J=4.1, 1.9, 1H),8.68 (m, 2H), 8.22 (td, J=7.9, 1.7, 1H), 8.12 (d, J=2.3, 1H), 8.07 (dd,J=8.4, 1.9, 1H), 7.60 (m, 4H), 7.48 (td, J=7.6, 1.0, 1H), 7.42 (dd,J=11.6, 8.2, 1H), 4.25 (s, 3H).

Example 40 Synthesis of Compound 80

A suspension of 227 mg (0.75 mmol)2-(2-fluoro-phenyl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridinein 2 ml pyridine was treated with 85 μl (0.91 mmol) benzoyl chloride.The mixture was stirred for 2 h at room temperature. Then 1.2 ml (15mmol) propylamine were added and the reaction mixture was stirred for 16hours at room temperature. Water was added to the reaction mixture; theresulting precipitate was filtered off, washed with water and dried. Theresidue was chromatographed on a silica gel column withdichloromethane/methanol as eluent yielding5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-2H-[2,6]naphthyridin-1-oneas yellow crystals; HPLC/MS (A) 1.67 min, [M+H] 369.

Example 41 Synthesis of Compound 62

-   1. 200 mg (1.35 mmol) of 6-aminoisoquinoline were disolved in 20 ml    of acetonitrile. 239,568 mg (1,35 mmol) of N-bromsuccinimide was    added. The reaction mixture was stirred for 4 h at room temperature.    The reaction mixture was evaporated and dichloromethane was added.    The organic phase was washed with water and dried. 224 mg of    5-bromo-isoquinolin-6-ylamine were obtained; HPLC/MS (B) 1.00 min,    [M+H] 224.-   2.    5-[2-(2-Fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoquinolin-6-ylamine    was obtained using the method described in example 6; H PLC/MS (B)    1.48 min, [M+H] 367.

Example 42 Synthesis of Compound 66

The title compound1-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-3-ylaminewas obtained from 1-bromo-[2,6]naphthyridin-3-ylamine and2-(2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid using methodsdescribed in example 6; HPLC/MS (A) 1.66 min, [M+H] 368

¹H NMR (500 MHz, DMSO) δ=9.22-9.11 (m, 2H), 8.19 (td, 1H), 8.12-7.95 (m,3H), 7.66-7.54 (m, 2H), 7.50-7.34 (m, 2H), 7.15 (d, J=9.8, 1 H), 6.97(s, 1H), 6.56 (br, 21H).

Example 43 Synthesis of Compound 70

The title compound2-(2-fluoro-phenyl)-4-(6-methoxy-isoguinolin-5-yl)-[1,8]naphthyridinewas prepared using the methods described in Example 6; HPLC/MS (A) 1.53min, [M+H] 382

¹H NMR (500 MHz, DMSO) δ 9.35 (d, J=0.6, 1H), 9.15 (dd, J=4.1, 1.9, 1H),8.43 (d, J=9.1, 1H), 8.28 (d, J=6.0, 1H), 8.20 (td, J=7.9, 1.8, 1H),7.94 (d, J=2.4, 1H), 7.85 (d, J=9.2, 1H), 7.74 (dd, J=8.3, 1.9, 1H),7.65-7.56 (m, 1H), 7.53 (dd, J=8.3, 4.1, 1H), 7.47 (td, J=7.6, 1.0, 1H),7.40 (ddd, J=11.6, 8.3, 0.8, 1H), 7.00 (d, J=6.0, 1H), 3.86 (s, 3H).

Example 44 Synthesis of Compound 85

The title compoundN-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-ylFisoguinolin-6-yl}-acetamidewas obtained after acetylation of5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-isoguinolin-6-ylamineusing acetic acid anhydride; HPLC/MS (A) 1.49 min, [M+H] 409

Example 45 Synthesis of Compound 117

-   1. A slurry of 900 mg (0.50 mmol)    2-(2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine in    5 ml 2-propanol was treated with 0.88 ml (5.1 mmol) peracetic acid    (38 - 49%) and the reaction mixture was stirred for 18 hours at room    temperature. Saturated sodium hydrogen carbonate solution was added    to the reaction mixture. The precipitate was filtered off, washed    with water and dried. The filtrate was extracted with    dichloromethane, the organic phase was dried over sodium sulfate and    evaporated. The residue was combined with the precipitate and    chromatographed on a silica gel column with dichloromethane/methanol    as eluent yielding    2-(2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    8-oxide as yellow solid; HPLC/MS (B) 1.91 min, [M+H] 384.-   2. A suspension of 124 mg (0.325 mmol)    2-(2-fluoro-phenyl)-4-(2-oxy-isoquinolin-5-yl)-[1,8]naphthyridine    8-oxide in 0.7 ml pyridine was treated with 86 μl (1.1 mmol)    methanesulfonyl chloride and the resulting solution was stirred for    18 hours at 80° C. The reaction mixture was cooled to room    temperature and 230 mg (3.9 mmol) propylamine were added and the    resulting solution was stirred for 20 hours at room temperature. The    reaction mixture was partitioned between water and dichloromethane;    the organic phase was dried over sodium sulfate and evaporated. The    residue was chromatographed on a silica gel column with ethyl    acetate/methanol as eluent yielding    5-(1-amino-isoquinolin-5-yl)-7-(2-fluoro-phenyl)-[1,8]naphthyridin-2-ylamine    as yellow crystals, HPLC/MS (B) 1.57 min, [M+H] 382.

¹H NMR (500 MHz, DMSO) δ=8.37 (d, J=7.8, 1H), 8.14 (td, J=7.9, 1.8, 1H),7.71 (d, J=6.0, 1H), 7.64 (m, 2H), 7.53 (tdd, J=7.2, 5.1, 1.8, 1H), 7.50(d, J=2.4, 1H), 7.40 (td, J=7.7, 1.0, 1H), 7.34 (dd, J=12.1, 8.7, 1H),7.31 (d, J=9.0, 1H), 6.95 (s, 2H), 6.91 (s, 2H), 6.74 (d, J=9.0, 1H),6.32 (d, J=6.0, 1H).

Compound 114 was prepared similarly: HPLC/MS (B) 1.41 min, [M+H] 383;

¹H NMR (500 MHz, DMSO) δ=8.73 (d, J=5.7, 1H), 8.24 (d, J=5.6, 1H), 8.14(td, J=7.9, 1.8, 1H), 7.86 (d, J=6.0, 1H), 7.58 (d, J=2.3, 1H), 7.54 (m,1H), 7.38 (m, 4H), 7.28 (s, 2H), 6.95 (s, 2H), 6.77 (t, J=6.4, 1H), 6.49(d, J=6.2, 1H).

Example 46 Synthesis of Compound 116

-   1. A solution of 5.17 g (20 mmol)    4-chloro-2-(2-fluoro-phenyl)-[1,8]naphthyridine in 40 ml    chlorobenzene was treated with 2.05 ml (40 mmol) bromine and heated    to 80° C. The reaction mixture was stirred at this temperature for 3    days. The reaction mixture was cooled to room temperature; the    solids were filtered off and washed with chlorobenzene. The residue    was partitioned between dichloromethane and saturated sodium    hydrogen carbonate solution. The organic phase was dried over sodium    sulfate and evaporated. The residue was chromatographed on a silica    gel column yielding    6-bromo-4-chloro-2-(2-fluoro-phenyl)-[1,8]naphthyridine as yellow    crystals; HPLC/MS (A) 2.72 min, [M+H] 339.-   2. A suspension of 1.69 g (5.00 mmol)    6-bromo-4-chloro-2-(2-fluoro-phenyl)-[1,8]naphthyridine, 1.04 g    (5.00 mmol)    1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole,    2.12 g (10.0 mmol) tri-potassium phosphate trihydrate in 10 ml    1,2-dimethoxy-ethane was heated to 80° C. under nitrogen. Then 105    mg (0.15 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were    added. The reaction mixture was stirred at 80° C. for 2 days under    nitrogen. The reaction mixture was cooled to room temperature; water    was added the resulting precipitate was filtered off and washed with    water. The residue was dried under vacuum and crystallized from    acetone/isopropanol yielding    4-chloro-2-(2-fluoro-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,8]naphthyridine    as off-white crystals; HPLC/MS (A) 2.35 min, [M+H] 339.-   3. A suspension of 1.25 g (3.68 mmol)    4-chloro-2-(2-fluoro-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,8]naphthyridine,    1.22 g (4.78 mmol) bis-pinacolato-diboron and 1.08 g (11.1 mmol)    anhydrous potassium acetate in 8 ml THF was heated to 80° C. under    nitrogen. Then 52 mg (0.074 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride were added and the    reaction mixture was stirred for 16 hours at 80° C. The mixture was    cooled to room temperature, treated with 0.3 ml acetic acid and    stirred for 30 minutes at room temperature. The solids were filtered    off, washed successively with water, THF, water and THF. The residue    was dried under vacuum yielding    [2-(2-fluorophenyl)-6-(1-methylpyrazol-4-yl)-1,8-naphthyridin-4-yl]boronic    acid as black solid; HPLC/MS (A) 1.77 min, [M+H] 349.-   4. A suspension of 181 mg (1.00 mmol) 1-chloro-[2,6]naphthyridine    6-oxide, 383 mg (1.1 mmol)    [2-(2-fluorophenyl)-6-(1-methylpyrazol-4-yl)-1,8-naphthyridin-4-yl]boronic    acid and 14 mg (0.02 mmol)    bis-(triphenylphosphine)-palladium(II)-chloride in 2 ml DMF was    heated to 80° C. under nitrogen. Then a solution of 101 mg (1.2    mmol) sodium hydrogen carbonate in 1 ml water was added. The    reaction mixture was stirred for 3 days at 80° C. Water was then    added to the reaction mixture and the resulting precipitate was    filtered off. The residue was washed with water and dried under    vacuum yielding    2-(2-fluoro-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine    as grey solid; HPLC/MS (A) 1.73 min, [M+H] 449.-   5. 55.4 μl (0.72 mmol) methanesulfonyl chloride was added slowly to    a suspension of 267 mg (0.60 mmol)    2-(2-fluoro-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-oxy-[2,6]naphthyridin-1-yl)-[1,8]naphthyridine    in 1.2 ml pyridine. The mixture was stirred for 1 hour at room    temperature and then 1.0 ml propylamine was added. The reaction    mixture was stirred for 18 hours at room temperature. Water was    added to the reaction mixture and the resulting precipitate was    filtered off and washed with water. The residue was chromatographed    on a silica gel column with methanol/ethyl acetate as eluent    yielding    5-[2-(2-fluoro-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine    as yellow crystals; HPLC/MS (A) 1.59 min, [M+H] 448.

¹H NMR (400 MHz, DMSO) δ=9.48 (d, J=2.5, 1H), 8.79 (d, J=5.7, 1H), 8.30(m, 2H), 8.20 (td, J=7.9, 1.8, 1H), 7.99 (m, 3H), 7.86 (d, J=6.0, 1H),7.60 (ddd, J=15.3, 5.2, 1.8, 1H), 7.46 (td, J=7.6, 1.0, 1H), 7.40 (dd,J=11.6, 8.3, 1H), 7.31 (s, 2H), 6.57 (d, J=5.9, 1 H), 3.84 (s, 3H).

Example 47 Synthesis of Compound 83 and Compound 92

Example 48 Synthesis of Compound 118

Example 49 Synthesis of Different Salts Forms of Compound 14

A suspension of 3.25 g (8.84 mmol)5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylaminein 90 ml 2-propanol was heated to 80° C. under stirring. Then 1.13 g(9.72 mmol) maleic acid was added and the reaction mixture was stirredfor 3 hours at 80° C. The reaction mixture was cooled to roomtemperature. The solid was filtered off and washed with 2-propanol andtert.butylmethylether. The residue was dried under vacuum yielding5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylaminemaleate as beige crystals.

¹H NMR (500 MHz, DMSO) δ=9.20 (dd, J=4.1, 1.9, 1H), 8.91 (d, J=5.7, 1H),8.44 (d, J=5.7, 1H), 8.21 (m, 3H), 8.09 (d, J=2.2, 1H), 7.98 (dd, J=8.4,1.9, 1H), 7.78 (d, J=6.5, 1H), 7.62 (m, 2H), 7.47 (td, J=7.6, 1.0, 1H),7.42 (dd, J=11.6, 8.3, 1H), 6.63 (d, J=6.5, 1H), 6.19 (s, 2H).

The following salts were prepared analogously:

-   (a)    5-[2-(2-Fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine    hydrochloride,-   (b)    5-[2-(2-Fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine    bis-methanesulfonate(dimesylate) (using 2.2 equivalents    methanesulfonic acid): yellow crystals; ¹H NMR (400 MHz, DMSO)    δ=9.66 (s, 1H), 9.33 (dd, J=4.6, 1.8, 1H), 9.12 (d, J=5.7, 1H), 8.67    (d, J=5.9, 1H), 8.31 (dd, J=8.4, 1.8, 1H), 8.26 (d, J=2.0, 1H), 8.22    (td, J=7.9, 1.8, 1H), 7.81 (dd, J=8.4, 4.6, 1H), 7.67 (m, 2H), 7.50    (td, J=7.6, 1.0, 1 H), 7.45 (dd, J=11.7, 8.3, 1 H), 6.84 (m, 2H),    2.45 (s, 6H),-   (c)    5-[2-(2-Fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine    sulphate,-   (d)    5-[2-(2-Fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyndin-1-ylamine    phosphate.

II. Assays

Example 50 In-Vitro (Enzyme) Assay for Determination of the Efficacy ofInhibitors of the Inhibition of TGF-Beta-Mediated Effects

The kinase assay was carried out as 384-well flashplate assay. 31.2 nMof GST-ALK5, 439 nM of GST-SMAD2 and 3 mM of ATP (with 0.3 μCi of³³P-ATP/well) were incubated in a total volume of 35 μl (20 mM of HEPES,10 mM of MgCl₂, 5 mM of MnCl₂, 1 mM of DTT, 0.1% of BSA, pH 7.4) withoutor with test substance (5-10 concentrations) at 30° C. for 45 min. Thereaction was stopped using 25 μl of 200 mM EDTA solution, filtered withsuction at room temperature after 30 min, and the wells were washed with3 times 100 μl of 0.9% NaCl solution. Radioactivity was measured in theTopCount. The IC₅₀ values were calculated using RS1. The results aregiven in Table 2.

Example 51 Inhibition of Smad2/3 Phosphorylation in Mv1 Lu Cells byTGF-Beta Receptor I Kinase Inhibitors

This assay was used to determine the inhibitory potency of compounds onTGF-beta-induced phosphorylation of Smad2 (Ser465/467) and Smad3(Ser423/425). Mv1-Lu cells (lung epithelial cell line from mink Mustelavison; ATCC number: CCL-64) were seeded in DMEM (Invitrogen)supplemented with 10% fetal bovine serum (Pan Biotech) at a defined celldensity in 24-well or 96-well plates (24-well plate: 1.5×105 cells perwell; 96-well plate: 4×10⁴ cells per well). Cell cultures were incubatedin DMEM at 37° C. and 10% CO₂. On the next day, the medium was replacedand cells were serum-starved for 16-20 hours. The following day, serialdilutions of compounds were added to the wells, pre-incubated for 1.5hrs before recombinant TGF-beta 1 ligand (final concentration 5 ng/ml;R&D systems) was added. After one hour of ligand stimulation, lysateswere prepared and analyzed using an enzyme-linked immunosorbent assaykit (PathScan Phospho-Smad2 Kit, Cell Signaling Technologies). The ELISAdetects phosphorylated Smad2 as well as phosphorylated Smad3 with thephospho-specific antibody. TGF-beta stimulated cells and unstimulatedcells served as positive and negative controls (100% and backgroundcontrol). The concentration of the vehicle DMSO was kept constant at0.2% (v/v) in all wells. Dose-response relationships were fitted usingcurve fitting algorithms of the RS1 statistics software package (BrooksAutomation Inc. RS/1- Statistical Tools Handbook. Release 6.2) todetermine the concentration at which half-maximal inhibition (IC₅₀) ofSmad2/3 phosphorylation was achieved. The results are given in Table 2.

TABLE 2 TβR activity TβR activity (Example 50) (Example 51) 0 >10 μM0 >10 μM HPLC/MS HPLC/MS + 1-10 μM + 1-10 μM Compound Name Rt. [min][M + H] ++ <1 μM ++ <1 μM 1 2-(5-Chloro-2- 1.57 375 ++ ++ fluoro- (A)phenyl)-4- (1H- pyrrolo[2,3- c]pyridin-3-yl)- [1,8]naphthyridine formate2 2-(5-Chloro-2- 2.10 386 ++ ++ fluoro- (A) phenyl)-4- isoquinolin-5-yl- [1,8]naphthyridine 3 2-(2-Fluoro-5- 1.58 409 ++ ++ trifluoromethyl-(A) phenyl)-4- (1H- pyrrolo[2,3- c]pyridin-3-yl)- [1,8]naphthyridine 45-[2-(5- 1.65 401 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-1- ylamine 5 2-(5-Chloro-2- 1.63433 ++ fluoro- (A) phenyl)-4-[1- (2-methoxy- ethyl)-1H- pyrrolo[2,3-c]pyridin-3-yl]- [1,8]naphthyridine formate 6 5-[2-(6- 1.26 364 ++ ++Methyl- (A) pyridin-2-yl)- [1,8]naphthyridin- 4-yl]- isoquinolin-1-ylamine 7 2-(6-Methyl- 1.54 350 ++ + pyridin-2-yl)- (A) 4-[2,6]naphthyridin- 1-yl- [1,8]naphthyridine 8 5-[2-(2- 1.75 435 ++ ++Fluoro-5- (A) trifluoromethyl- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-1- ylamine 9 5-[2-(2- 1.51 367 ++ ++ Fluoro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-1- ylamine 10 5-[2-(2,5- 145 385++ ++ Difluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-1-ylamine 11 5-[2-(5- 1.46 402 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]- [2,6]naphthyridin- 1-ylamine 12 2-(5-Chloro-2-1.86 376 ++ ++ fluoro- (A) phenyl)-4- furo[2,3- c]pyridin-3-yl-[1,8]naphthyridine 13 3-[2-(5- 1.39 391 ++ ++ Chloro-2- (A) fluoro-phenyl)- [1,8]naphthyridin- 4-yl]- furo[2,3- c]pyridin-7- ylamine 145-[2-(2- 1.41 368 ++ ++ Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine 15 8-[2-(2- 1.41 368 + Fluoro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- quinazolin-4- ylamine 16 2-(2-Fluoro- 2.15 397++ phenyl)-4-(8- (A) nitro- isoquinolin-5- yl)- [1,8]naphthyridine 172-(2-Fluoro- 1.74 382 ++ ++ phenyl)-4-(8- (A) methoxy- isoquinolin-5-yl)- [1,8]naphthyridine 18 4-[2-(2- 1.91 354 + 0 Fluoro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- pyrido[3,4- d]pyrimidine 19 2-(2-Fluoro- 1.87352 ++ ++ phenyl)-4- (A) isoquinolin-5- yl- [1,8]naphthyridine 205-[2-(2,5- 1.38 386 ++ ++ Difluoro- (A) phenyl)- [1,8]naphthyridin-4-yl]- [2,6]naphthyridin- 1-ylamine hydrochloride 21 5-[2-(6- 1.10 365++ ++ Methyl- (A) pyridin-2-yl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine hydrochloride 22 5-[2-(5- 1.54 401 ++ ++Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-8-ylamine hydrochloride 23 2-(2-Fluoro- 1.93 353 + + phenyl)-4- (A)[2,6]naphthyridin- 1-yl- [1,8]naphthyridine 24 4-[2-(5- 2.09 388 ++ +Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- pyrido[3,4-d]pyrimidine 25 2-(2-Fluoro- 1.34 481 ++ ++ phenyl)-4-[8- (B)(2-morpholin- 4-yl-ethoxy)- isoquinolin-5- yl]- [1,8]naphthyridine 265-[2-(2- 1.59 397 Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-8-methoxy- isoquinolin-1- ylamine 32 1-[2-(2- 1.91 384 ++ 0 Fluoro- (A)phenyl)- [1,8]naphthyridin- 4-yl]-4- methoxy- pyrido[3,4- d]pyridazine35 2-(5-Chloro-2- 2.00 387 ++ ++ fluoro- (A) phenyl)-4-[2,6]naphthyridin- 1-yl- [1,8]naphthyridine 36 8-[2-(2- 1.47 369 0Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]- pyrido[3,4-d]pyrimidin-4- ylamine 37 5-[2-(5- 2.01 387 ++ + Chloro-2- (A) fluoro-phenyl)- [1,8]naphthyridin- 4-yl]- [1,7]naphthyridine 38 5-[2-(2,5- 1.50385 ++ ++ Difluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8- ylamine 39 2-{5-[2-(2- 1.53 412 ++ Fluoro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-8- yloxy}-ethanol 40 2-(2-Fluoro-2.33 383 0 0 phenyl)-4-(5- (A) methoxy- [2,6]naphthyridin-1- yl)-[1,8]naphthyridine 41 5-[2-(2- 1.33 367 ++ Fluoro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-8- ylamine 42 4-[2-(2- 1.40 368Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]- [2,7]naphthyridin-1-ylamine 48 5-[2-(2- 1.82 397 Fluoro- (A) phenyl)- [1,8]naphthyridin-4-yl]-8- methoxy- isoquinolin-3- ylamine 49 5-[2-(5- 2.06 401 0Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-3-ylamine 50 2-(5-Chloro-2- 2.30 431 fluoro- (A) phenyl)-4-(8- nitro-isoquinolin-5- yl)- [1,8]naphthyridine 62 5-[2-(2- 1.48 367 ++ + Fluoro-(A) phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-6- ylamine 642-(2-Fluoro- 1.87 432 + ++ phenyl)-4-[5- (A) (1-methyl-1H-pyrazol-4-yl)- isoquinolin-8- yl]- [1,8]naphthyridine 65 2-(2-Fluoro-1.84 432 ++ ++ phenyl)-4-[8- (A) (1-methyl-1H- pyrazol-4-yl)-isoquinolin-5- yl]- [1,8]naphthyridine 66 1-[2-(2- 1.66 368 ++ ++Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin-3-ylamine 67 4-[2-(2- 1.56 413 ++ + Fluoro- (A) phenyl)-[1,8]naphthyrin- 4-yl]-2-(2- hydroxy- ethyl)-2H- [2,7]naphthyridin-1-one 68 4-[2-(5- 1.74 447 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]-2-(2- hydroxy- ethyl)-2H- [2,7]naphthyridin-1-one 69 N-{5-[2-(2- 1.64 410 ++ Fluoro- (A) phenyl)- [1,8]naphthyridin-4-yl]- [2,6]naphthyridin- 1-yl}- acetamide 70 2-(2-Fluoro- 1.53 382 ++++ phenyl)-4-(6- (A) methoxy- isoquinolin-5- yl)- [1,8]naphthyridine 712- 1.64 453 + + Dimethylamino- (B) N-{5-[2-(2- fluoro- phenyl)-[1,8]naphthyridin- 4-yl]- [2,6]naphthyridin- 1-yl}- acetamide 724-[2-(2,5- 1.62 431 ++ ++ Difluoro- (A) phenyl)- [1,8]naphthyridin-4-yl]-2-(2- hydroxy- ethyl)-2H- [2,7]naphthyridin- 1-one 73 N-{5-[2-(2-1.76 440 + + Fluoro- (B) phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-yl}-2- methoxy- acetamide 74 4-[2-(5- 1.89 417 ++++ Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2- methyl-2H-[2,7]naphthyridin- 1-one 75 4-[2-(5- 1.78 461 ++ ++ Chloro-2- (A)fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2-(3- hydroxy- propyl)-2H-[2,7]naphthyridin- 1-one 76 4-[2-(5- 1.58 516 + + Chloro-2- (A) fluoro-phenyl)- [1,8]naphthyridin- 4-yl]-2-(2- morpholin-4- yl-ethyl)-2H-[2,7]naphthyridin- 1-one 77 2-(5-Chloro-2- 1.67 516 ++ ++ fluoro- (A)phenyl)-4-[1- (2-morpholin- 4-yl-ethoxy)- [2,7]naphthyridin- 4-yl]-[1,8]naphthyridine 78 2-(2-Fluoro- 1.50 482 ++ + phenyl)-4-[1- (A)(2-morpholin- 4-yl-ethoxy)- [2,7]naphthyridin- 4-yl]- [1,8]naphthyridine79 2-{1-Amino-5- 1.79 427 ++ ++ [2-(2-fluoro- (B) phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-8- yloxy}-ethanol 80 5-[2-(2- 1.67369 Fluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-2H- [2,6]naphthyridin-1-one 81 4-[2-(5- 1.67 477 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]-2- (2,3- dihydroxy- propyl)-2H-[2,7]naphthyridin- 1-one 82 (2-{5-[2-(5- 1.40 473 ++ ++ Chloro-2- (A)fluoro- phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-8- yloxy}-ethyl)-dimethyl- amine 83 2-(5-Chloro-2- 2.47 420 ++ ++ fluoro- (A)phenyl)-4-(8- chloro- isoquinolin-5- yl)- [1,8]naphthyridine 84 5-[2-(5-1.52 354 ++ ++ Methyl-furan- (B) 2-yl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine 85 N-{5-[2-(2- 1.49 409 + 0 Fluoro- (A)phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-6- yl}-acetamide 86(2-{5-[2-(5- 1.46 501 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]- isoquinolin-8- yloxy}-ethyl)- diethyl-amine 875-(2-Phenyl- 1.36 350 ++ ++ [1,8]naphthyridin- (A) 4-yl)-[2,6]naphthyridin- 1-ylamine 88 2-(2-Fluoro- 1.60 369 0 0 phenyl)-4-(6-(A) oxy- [2,6]naphthyridin- 1-yl)- [1,8]naphthyridine 89 4-[2-(5- 1.69403 ++ ++ Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2H-[2,7]naphthyridin- 1-one 90 5-[2-(2- 1.42 384 ++ + Chloro- (A) phenyl)-[1,8]naphthyridin- 4-yl]- [2,6]naphthyridin- 1-ylamine 91 4-[2-(5- 1.43500 ++ ++ Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2-(2-pyrrolidin-1-yl- ethyl)-2H- [2,7]naphthyridin- 1-one 92 N′-{5-[2-(5-1.45 500 ++ ++ Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-isoquinolin-8- yl}-N,N- diethyl- ethane-1,2- diamine 93 2-Phenyl-4- 323(1H- pyrrolo[2,3- b]pyridin-3- yl)- [1,8]naphthyridine 94 2-(2,6- 383Dimethoxy- phenyl)-4- (1H- pyrrolo[2,3- b]pyridin-3- yl)-[1,8]naphthyridine 95 4-(1H- 391 Pyrrolo[2,3- b]pyridin-3- yl)-2-(3-trifluoromethyl- phenyl)- [1,8]naphthyridine 96 2-(2-Fluoro-5- 409trifluoromethyl- phenyl)-4- (1H- pyrrolo[2,3- b]pyridin-3- yl)-[1,8]naphthyridine 97 2-(4-Fluoro-2- 355 methyl- phenyl)-4- (1H-pyrrolo[2,3- b]pyridin-3- yl)- [1,8]naphthyridine 98 (2-{4-[2-(5- 1.62502 ++ ++ Chloro-2- (A) fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-[2,7]naphthyridin- 1-yloxy}- ethyl)-diethyl- amine 99 2-(2,5- 1.80 400++ ++ Difluoro- (A) phenyl)-4-(8- methoxy- isoquinolin-5- yl)-[1,8]naphthyridine 100 2-(5-Chloro-2- 1.55 500 ++ ++ fluoro- (A)phenyl)-4-[1- (2-pyrrolidin- 1-yl-ethoxy)- [2,7]naphthyridin- 4-yl]-[1,8]naphthyridine 101 2-Furan-2-yl- 1.18 313 ++ ++ 4-(1H- (A)pyrrolo[2,3- c]pyridin-3-yl)- [1,8]naphthyridine 102 2-(5-Chloro-2- 1.40499 ++ ++ fluoro- (A) phenyl)-4-[8- (2-pyrrolidin- 1-yl-ethoxy)-isoquinolin-5- yl]- [1,8]naphthyridine 103 (2-{5-[2-(2,5- 1.42 485 ++ ++Difluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]- isoquinolin-8-yloxy}-ethyl)- diethyl-amine 104 4-[2-(5- 1.47 502 + + Chloro-2- (A)fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-2-(2- diethylamino- ethyl)-2H-[2,7]naphthyridin- 1-one 105 4-(1H- 391 Pyrrolo[2,3- b]pyridin-3-yl)-2-(4- trifluoromethyl- phenyl)- [1,8]naphthyridine 107 4-[2-(2,5-1.57 387 ++ ++ Difluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-2H-[2,7]naphthyridin- 1-one 108 2-(2-Methyl- 1.25 327 ++ ++ furan-3-yl)-4-(A) (1H- pyrrolo[2,3- c]pyridin-3-yl)- [1,8]naphthyridine 109 5-[2-(2,6-1.36 386 ++ 0 Difluoro- (A) phenyl)- [1,8]naphthyridin- 4-yl]-[2,6]naphthyridin- 1-ylamine 110 4-[2-(5- 1.59 516 + 0 Chloro-2- (A)fluoro- phenyl)- [1,8]naphthyridin- 4-yl]-1-(2- morpholin-4-yl-ethyl)-1H- [1,7]naphthyridin- 2-one 111 4-[2-(2- 2.30 353 ++ 0Fluoro- (B) phenyl)- [1,8]naphthyridin- 4-yl]- [1,7]naphthyridine 1124-[2-(5- 1.64 516 ++ ++ Chloro-2- (A) fluoro- phenyl)-[1,8]naphthyridin- 4-yl]-2-(2- morpholin-4- yl-ethoxy)-[1,7]naphthyridine 113 4-[2-(2- 1.75 368 ++ ++ Fluoro- (B) phenyl)-[1,8]naphthyridin- 4-yl]- [1,7]naphthyridin- 8-ylamine 114 5-(5-Amino-1.41 383 ++ ++ [2,6]naphthyridin- (B) 1-yl)-7-(2- fluoro- phenyl)-[1,8]naphthyridin- 2-ylamine 115 2-(2-Fluoro- 2.49 353 ++ ++phenyl)-4-(4- (B) methoxy- [2,6]naphthyridin- 1-yl)- [1,8]naphthyridine116 5-[2-(2- 1.59 448 0 0 Fluoro- (A) phenyl)-6-(1- methyl-1H-pyrazol-4-yl)- [1,8]naphthyridin- 4-yl]- [2,6]naphthyridin- 1-ylamine117 5-(1-Amino- 1.57 382 ++ ++ isoquinolin-5- (B) yl)-7-(2-fluoro-phenyl)- [1,8]naphthyridin- 2-ylamine 118 2-(3-Methyl- 1.29 327 ++ ++pyrazol-1-yl)- (A) 4-(1H- pyrrolo[2,3- c]pyridin-3-yl)-[1,8]naphthyridine 119 4-Isoquinolin- 1.63 338 5-yl-2-(2- (A)methyl-furan- 3-yl)- [1,8]naphthyridine 120 2-(2-Fluoro- 342 phenyl)-4-(5H- pyrrolo[2,3- b]pyrazin-7- yl)- [1,8]naphthyridine

1. Compounds of formula (I)

wherein: W₁, W₂, W₃, W₄denotes independently from each other N or CR³,W₅ denotes N or C, preferably denotes N or CR³, more preferably denotesN, Z denotes C═C, NR⁴, C═N, O, S, CH, N═N or N═C, preferably denotesC═C, N(R⁴)CO, NR⁴, C═N, O, CON(R⁴), S, CH, N═N or N═C, more preferablydenotes C═C, N(R⁴)CO, NR⁴, C═N, O, CON(R⁴), S, CH or N═N, R¹ denotes amonocyclic aryl having 5, 6, 7, 8, 9 or 10 C atoms or a monocyclicheteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms and 1, 2,3, 4 or 5 N, O and/or S atoms, each of which can be independentlysubstituted by at least one substituent selected from the groupconsisting of Y, Hal, CN, CF₃ or OY, R² denotes H, Hal, A,—(CYY)_(n)—OY, —(CYY)_(n)—NYY, —(CYY)_(n)— Het, SY, NO₂, CN, COOY,—CO—NYY, —NY—COA, —NY—SO₂A, —SO₂—NYY, S(O)_(m)A, —CO-Het,—O(CYY)_(n)—OY, —O(CYY)_(n)—NYY, —O(CYY)_(n)-Het, —NH—COOA, —NH—CO—NYY,—NH—COO—(CYY)_(n)—NYY, —NH—COO—(CYY)_(n)-Het, —NH—CO—NH—(CYY)_(n)—NYY,—NH—CO—NH(CYY)_(n)-Het, —OCO—NH—(CYY)_(n)—NYY, —OCO—NH—(CYY)_(n)-Het,CHO, COA, ═S, ═NY, ═O or a monocyclic aryl having 5, 6, 7, 8, 9 or 10 Catoms or a monocyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13 or14 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, each of monocyclicaryl and monocyclic heteroaryl can be independently substituted by atleast one substituent selected from the group consisting of Y, Hal, CN,CF₃ or OY, R³ denotes H, OY, NYY, NY—COY, NY—CO—(CYY)_(n)—OY,NY—COY—NYY, NY—(CYY)_(n) —NYY, O—(CYY)_(n) —NYY or O—(CYY)_(n)-Het, R⁴denotes H, A, —(CYY)_(o)-Het, ‘(CYY)_(o)—NYY or —(CYY)_(o)—OY, R⁵denotes H, A, OY, NYY or Het, Y denotes H or A, preferably in case of—(CYY)_(/o)—Y additionally denotes H, A or OH, A denotes unbranched orbranched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, in which1, 2, 3, 4, 5, 6 or 7 H atoms can be replaced independently from oneanother by Hal and/or in which one or two CH₂ groups can be replacedindependently of one another by a O, S, SO, SO₂, a —CY═CY— group and/ora —C≡C— group; alternatively, A denotes cycloalkyl with 3, 4, 5, 6, 7 or8 C-atoms, Het denotes a saturated or unsaturated, mono, bi- ortricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 C atoms and 1, 2, 3, 4 or 5 N, O and/or Satoms, which can be substituted by at least one substituent selectedfrom the group consisting of Y, Hal, CN, CF₃, OY, Hal denotes F, Cl, Bror I, m denotes 0, 1 or 2, n denotes 0, 1, 2, 3 or 4, o denotes 0, 1, 2,3 or 4, preferably if Z is NR⁴, o additionally denotes 2, 3 or 4, pdenotes 0, 1, 2 or 3, q denotes 0, 1, 2 or 3, with the proviso that thefollowing compounds are excluded: (a)2-(5-chloro-2-fluoro-phenyl)-4-isoquinolin-4-yl-[1,8]naphthyridine, (b)4-isoquinolin-4-yl-2-(6-methyl-pyridin-2-yl)-[1,8]naphthyridine, (c)4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,(d)4-[2-(2,5-difluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,(e)N-{4-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-yl}-acetamide,(f) 2-(2-fluoro-phenyl)-4-[2,7]naphthyridin-4-yl-[1,8]naphthyridine, (g)5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine,(h)5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[1,7]naphthyridine,(i)4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,7]naphthyridin-1-ylamine, and the physiologically acceptable salts, solvates,stereoisomers and tautomers thereof, including mixtures thereof in allratios.
 2. Compound according to claim 1, with the further proviso thatW₅ denotes N and/or Z excludes N═C, i.e. Z denotes C═C, N(R⁴)CO, NR⁴,C═N, O, CON(R⁴), S, CH or N═N, and the physiologically acceptable salts,solvates, stereoisomers and tautomers thereof, including mixturesthereof in all ratios.
 3. Compound according to claim 1, wherein Z isselected from the group consisting of: (a) C═C, or (b) N(R⁴)CO, or (c)NR⁴, or (d) C═N, or (e) O, or (f) CON(R⁴), and preferably is C═C, andthe physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.
 4. Compoundaccording to claim 1, wherein (a) W₁, W₃, W₄ denote independently fromeach other CR³, and W₂ denotes N, or (b) W₂, W₃, W₄ denote independentlyfrom each other CR³, and W₁ denotes N, or (c) W₁, W₂, W₄ denoteindependently from each other CR³, and W₃ denotes N, or (d) W₁, W₂, W₃,W₄ denote independently from each other CR³, or (e) W₁, W₃ denoteindependently from each other CR³, and W₂, W₄ denotes N, and thephysiologically acceptable salts, solvates, stereoisomers and tautomersthereof, including mixtures thereof in all ratios.
 5. Compound accordingto claim 1, wherein R¹ denotes phenyl, which can be substituted by atleast one substituent selected from the group consisting of Y, Hal, CN,CF₃ or OY, and the physiologically acceptable salts, solvates,stereoisomers and tautomers thereof, including mixtures thereof in allratios.
 6. Compound according to claim 1, wherein R² is absent ordenotes H, A, Hal, —(CYY)_(n)—OY, NO₂, —(CYY)_(n)—NYY, —(CYY)_(n)-Het,—O—(CYY)_(n)-Het, —O—(CYY)_(n)—OY, —O—(CYY)_(n)—NYY, NY—(CYY)_(n)—NYY,NY—COY or a monocyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13or 14 C atoms and 1, 2, 3, 4 or 5 N, O and/or S atoms, where themonocyclic heteroaryl can be independently substituted by at least onesubstituent selected from the group consisting of Y, Hal, CN, CF₃ or OY,and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.
 7. Compoundaccording to claim 1, wherein W₁, W₃, W₄ denote independently from eachother CR³, and W₂, W₅ denote N, and Z denotes C═C, and R¹ denotesphenyl, which can be substituted by at least one substituent selectedfrom the group consisting of Y, Hal, CN, CF₃ or OY, and thephysiologically acceptable salts, solvates, stereoisomers and tautomersthereof, including mixtures thereof in all ratios.
 8. Compoundsaccording to claim 1, which are selected from the group consisting of:

and the physiologically acceptable salts, solvates, stereoisomers andtautomers thereof, including mixtures thereof in all ratios.
 9. Processfor manufacturing a compound of formula (I) comprising the steps of: (a)reacting a compound of formula (II)

wherein R⁶ denotes Hal or B(OH)₂, and R¹, R⁵, q and Hal have the meaningas defined above, with a compound of formula (III)

wherein R⁷ denotes Hal, boronic acid or a ester of boronic acid, and R²,p, Z, W₁, W₂, W₃, W₄, W₅ and Hal have the meaning as defined above, toyield the compound of formula (I)

wherein R¹, R², R⁵, p, q, Z, W₁, W₂, W₃, W₄, and W₅ have the meaning asdefined above, or b) reacting a compound of formula (IV)

wherein R¹, R², R⁵, p, q, Z, W₁, W₃, W₄, and W₅ have the meaning asdefined above, with alkyl- or arylsulfonylchloride, such asmethanesulfonylchloride or p-toluenesulfonylchloride, pyridine oralkyl-pyridine and a primary alkylamine, such as ethanolamine,propylamine or butylamine, to yield the compound of formula (I′) and/or(I″)

wherein R¹, R², R⁵, p, q, Z, W₁, W₃, W₄, and W₅ have the meaning asdefined above and for formula (I′) W₁ is CR³ with R³ being NYY and Ybeing H and W₂ is N and for formula (I″) W₃ is CR³ with R³ being NYY andY being H and W₂ is N, and optionally (c) converting a base or an acidof the compound of formula (I), (I′) or (I″) into a salt thereof.
 10. Amethod for inhibiting ATP consuming proteins, preferably TGF-betareceptor kinase, RON, TAK1, PKD1, MINK1, SAPK2-alpha, SAPK2-beta and/orCHK2, comprising administering to a subject in need thereof an effectiveamount of a compound of claim
 1. 11. (canceled)
 12. A method for thetreatment and/or prophylaxis of physiological and/or pathophysiologicalconditions selected from the group consisting of: cancer, tumour,malignant tumours, benign tumours, solid tumours, sarcomas, carcinomas,hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposisarcomas, brain tumours, tumours originating from the brain and/or thenervous system and/or the meninges, gliomas, glioblastomas,neuroblastomas, stomach cancer, kidney cancer, kidney cell carcinomas,prostate cancer, prostate carcinomas, connective tissue tumours, softtissue sarcomas, pancreas tumours, liver tumours, head tumours, necktumours, laryngeal cancer, oesophageal cancer, thyroid cancer,osteosarcomas, retinoblastomas, thymoma, testicular cancer, lung cancer,lung adenocarcinoma, small cell lung carcinoma, bronchial carcinomas,breast cancer, mamma carcinomas, intestinal cancer, colorectal tumours,colon carcinomas, rectum carcinomas, gynaecological tumours, ovarytumours/ovarian tumours, uterine cancer, cervical cancer, cervixcarcinomas, cancer of body of uterus, corpus carcinomas, endometrialcarcinomas, urinary bladder cancer, urogenital tract cancer, bladdercancer, skin cancer, epithelial tumours, squamous epithelial carcinoma,basaliomas, spinaliomas, melanomas, intraocular melanomas, leukaemias,monocyte leukaemia, chronic leukaemias, chronic myelotic leukaemia,chronic lymphatic leukemia, acute leukaemias, acute myelotic leukaemia,acute lymphatic leukemia, lymphomas, opthalmic diseases, choroidalneovascularization, diabetic retinopathy, inflammatory diseases,arthritis, neurodegeneration, transplant rejection, metastatic growth,fibrosis, restenosis, HW infection, atherosclerosis, inflammation anddisorders of wound healing, angiogenesis, cardiovascular system, bone,CNS and/or PNS, comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 13. (canceled)
 14. The methodaccording to claim 12, wherein the compound is applied before and/orduring and/or after treatment with at least one additionalpharmacologically active substance.
 15. Pharmaceutical compositioncomprising at least one compound according to claim 1, and at least oneadditional compound selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and additional pharmaceutically active substance other than thecompound of formula I.
 16. Kit comprising at least one compoundaccording to claim 1, and at least one further pharmacologically activesubstance other than the compound of formula I.
 17. The compositionaccording to claim 15, which comprises at least one additionalpharmacologically active substance.